Pyrazine compounds as phosphodiesterase 10 inhibitors

ABSTRACT

Pyrazine compounds, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/619,574, filed 16 Nov. 2009, which claims the benefit from U.S.Provisional Application No. 61/114,567, filed 14 Nov. 2008, and U.S.Provisional Application No. 61/166,212, filed 2 Apr. 2009, each of whichis hereby incorporated by reference.

FIELD OF THE INVENTION

Provided herein are certain pyrazine compounds that are PDE10inhibitors, pharmaceutical compositions containing such compounds, andprocesses for preparing such compounds. Provided herein also are methodsof treating disorders or diseases treatable by inhibition of PDE10, suchas obesity, non-insulin dependent diabetes, schizophrenia, bipolardisorder, obsessive-compulsive disorder, and the like.

BACKGROUND

Neurotransmitters and hormones, as well as other types of extracellularsignals such as light and odors, create intracellular signals byaltering the amounts of cyclic nucleotide monophosphates (cAMP and cGMP)within cells. These intracellular messengers alter the functions of manyintracellular proteins. Cyclic AMP regulates the activity ofcAMP-dependent protein kinase (PKA). PKA phosphorylates and regulatesthe function of many types of proteins, including ion channels, enzymes,and transcription factors. Downstream mediators of cGMP signaling alsoinclude kinases and ion channels. In addition to actions mediated bykinases, cAMP and cGMP bind directly to some cell proteins and directlyregulate their activities.

Cyclic nucleotides are produced from the actions of adenylyl cyclase andguanylyl cyclase, which convert ATP to cAMP and GTP to cGMP.Extracellular signals, often through the actions of G protein-coupledreceptors, regulate the activities of the cyclases. Alternatively, theamount of cAMP and cGMP may be altered by regulating the activities ofthe enzymes that degrade cyclic nucleotides. Cell homeostasis ismaintained by the rapid degradation of cyclic nucleotides afterstimulus-induced increases. The enzymes that degrade cyclic nucleotidesare called 3′,5′-cyclic nucleotide-specific phosphodiesterases (PDEs).

Eleven PDE gene families (PDE1-PDE11) have been identified based ontheir distinct amino acid sequences, catalytic and regulatorycharacteristics, and sensitivity to small molecule inhibitors. Thesefamilies are coded for by 21 genes; and further multiple splice variantsare transcribed from many of these genes. Expression patterns of each ofthe gene families are distinct. PDEs differ with respect to theiraffinity for cAMP and cGMP. Activities of different PDEs are regulatedby different signals. For example, PDE1 is stimulated byCa²⁺/calmodulin. PDE2 activity is stimulated by cGMP. PDE3 is inhibitedby cGMP. PDE4 is cAMP specific and is specifically inhibited byrolipram. PDE5 is cGMP-specific. PDE6 is expressed in retina.

PDE10 sequences were identified by using bioinformatics and sequenceinformation from other PDE gene families (Fujishige et al., J. Biol.Chem. 274:18438-18445, 1999; Loughney et al., Gene 234:109-117, 1999;Soderling et al., Proc. Natl. Acad. Sci. USA 96:7071-7076, 1999). ThePDE10 gene family is distinguished based on its amino acid sequence,functional properties and tissue distribution. The human PDE10 gene islarge, over 200 kb, with up to 24 exons coding for each of the splicevariants. The amino acid sequence is characterized by two GAF domains(which bind cGMP), a catalytic region, and alternatively spliced N and Ctermini. Numerous splice variants are possible because at least threealternative exons encode N termini and two exons encode C-termini.PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP.The K_(m) values for cAMP and cGMP are 0.05 and 3.0 micromolar,respectively. In addition to human variants, several variants with highhomology have been isolated from both rat and mouse tissues and sequencebanks.

PDE10 RNA transcripts were initially detected in human testis and brain.Subsequent immunohistochemical analysis revealed that the highest levelsof PDE10 are expressed in the basal ganglia. Specifically, striatalneurons in the olfactory tubercle, caudate nucleus and nucleus accumbensare enriched in PDE10. Western blots did not reveal the expression ofPDE10 in other brain tissues, although immunoprecipitation of the PDE10complex was possible in hippocampal and cortical tissues. This suggeststhat the expression level of PDE10 in these other tissues is 100-foldless than in striatal neurons. Expression in hippocampus is limited tothe cell bodies, whereas PDE10 is expressed in terminals, dendrites andaxons of striatal neurons.

The tissue distribution of PDE10 indicates that PDE10 inhibitors can beused to raise levels of cAMP and/or cGMP within cells that express thePDE10 enzyme, for example, in neurons that comprise the basal gangliaand therefore would be useful in treating a variety of neuropsychiatricconditions involving the basal ganglia such as obesity, non-insulindependent diabetes, schizophrenia, bipolar disorder, obsessivecompulsive disorder, and the like.

SUMMARY OF THE INVENTION

The present invention comprises a new class of pyrazine compounds usefulin the treatment of diseases, such as PDE10-mediated diseases and othermaladies, such as schizophrenia, bipolar disorder, orobsessive-compulsive disorder. Accordingly, the invention also comprisespharmaceutical compositions comprising the compounds, methods for thetreatment of PDE10-mediated diseases and other maladies, such asschizophrenia, bipolar disorder, or obsessive-compulsive disorder, usingthe compounds and compositions of the invention, and intermediates andprocesses useful for the preparation of the compounds of the invention.

The compounds of the invention are represented by the following generalstructure:

or a pharmaceutically acceptable salt thereof, wherein m, n, p, R¹, R²,R³, R⁴, X¹, X², X³, X⁴, X⁵, X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, Y and Z aredefined below.

Other compounds of the invention are represented by the followinggeneral structure:

or a pharmaceutically acceptable salt thereof, wherein m, n, p, y, R²,R³, R⁴, R⁹, X⁵, and Z are defined below.

Other compounds of the invention are represented by the followinggeneral structure:

or a pharmaceutically acceptable salt thereof, wherein m, n, p, y, R²,R³, R⁴, R⁹, X¹, X⁵, and Z are defined below.

Other compounds of the invention are represented by the followinggeneral structure:

or a pharmaceutically acceptable salt thereof, wherein m, n, R¹, R², R³,R⁴, X¹, X², X³, X⁴, Y and Z are defined below.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents, patent applications and other publications recitedherein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the current invention relates to compounds having thegeneral structure of formula (I):

or any pharmaceutically-acceptable salt thereof, wherein:

Each of X¹, X², X³, X⁴, and X⁵ is independently N or C; wherein no morethan two of X¹, X², X³ and X⁴ are N;

Each of X⁶, X⁷, X⁹, and X¹⁰ is independently N or C; each of X⁸ and X¹¹is C; wherein no more than three of X⁶, X⁷, X⁹, and X¹⁰ are N;

Y is NH, NR⁵, CH(OH), C(═O), —CR^(a)R^(b), or CF₂; or alternatively Yand R³ form a 5- to 6-membered ring fused to the ring containing bothsaid Y and R³;

Z is NH, NR⁶, S, SO, SO₂, O, or C; wherein Z is only C when X⁵ is N;

m is 0, 1, 2, 3 or 4;

n is 0, 1 or 2;

p is 0, 1 or 2;

R¹ is selected from the group consisting of

(a) H, F, Cl, Br, I, C₁₋₈alk, C₁₋₄haloalk, —OR^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —C(═O)NR^(a)R^(a), —C(═O)R^(d), —C(═O)—O—R^(a),—OR^(c), —NR^(a)R^(c), —N(R^(c))C(═O)R^(b), —N(R^(a))C(═O)R^(c),—C(═O)NR^(a)R^(b), or —C(═O)NR^(a)R^(c);

(b) a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or7-membered monocyclic ring or a saturated, partially-saturated orunsaturated 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein eachsaid ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atomsselected from O and S, and wherein each said ring is substituted by 0,1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —NR^(a)R^(c),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆ alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁷, R⁸ and oxo;

(c) group -L-R⁷, wherein L is CH₂, NH, N(C₁₋₄alk),—C(═O)NR^(a)R^(a)(C₁₋₄alk), O, S, S═O, or S(═O)₂; or

(d) C₁₋₆alk substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a), R⁸ and oxo;

R² is, independently in each instance, F, Cl, Br, CN, OH, OC₁₋₄alk,C₁₋₄alk or C₁₋₄haloalk;

R³ is, independently in each instance, F, Cl, Br, CN, OH, OC₁₋₄alk,C₁₋₄alk, C₁₋₄haloalk, or —NR^(a)C₁₋₄alk;

R⁴ is independently in each instance, F, Cl, CH₃, CN, CF₃, CHF₂, CH₂F,OR^(a), or NR^(a)R^(a); R⁵ is C₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), orR^(c);

R⁶ is C₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), or R^(c);

R⁷ is a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or7-membered monocyclic or 8-, 9-, 10-, 11-, or 12-membered bicyclic ringcontaining 0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S,which is substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁸ and oxo;

R⁸ is a C₁₋₆alk substituted by 0, 1, 2 or 3 groups selected from F, Cl,Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo;

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk,—NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk;

R^(c) is a C₀₋₄alk-linked saturated, partially-saturated or unsaturated3-, 4-, 5-, 6-, or 7-membered monocyclic or 8-, 9-, 10-, 11-, or12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1atom selected from O and S, which is substituted by 0, 1, 2 or 3 groupsselected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, R⁷, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo; and

R^(d) is a nitrogen-linked saturated, partially-saturated, orunsaturated 5-, 6- or 7-membered ring heterocycle containing the linkingnitrogen and 0, 1 or 2 additional nitrogen atoms and containing 0 or 1sulfur or oxygen atom, the heterocycle being substituted by 0, 1, 2 or 3substituents selected from oxo, halo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk,—NH₂, —NHC₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk.

In another embodiment, the group:

is selected from the group consisting of;

In another embodiment, the group

In another embodiment, the group

In another embodiment, the group

In another embodiment, the group

In another embodiment, the group

In another embodiment, the group

In another embodiment, the group

In another embodiment, the group

In another embodiment, the group

In another embodiment, the group

In another embodiment, Y is NH, N—CH₃, CF₂, or —C(═O).

In another embodiment, Y is NH.

In another embodiment, Y is —C(═O).

In another embodiment, Y is —N—CH₂—C₆C₅—F.

In another embodiment, Y is —CH₂—.

In another embodiment, Y and R³ form a 5- to 6-membered ring fused tothe ring containing both said Y and R³; wherein Y is NH, and R³ isC₁₋₄alk or —NR^(a)C₁₋₄alk.

In another embodiment, X^(i) is N or C, and each of X², X³, X⁴, and X⁵is C.

In another embodiment, X⁵ is N.

In another embodiment, X⁵ is C.

In another embodiment, Z is NH, N—C₁₋₄alk, N-haloC₁₋₄alk, S, or —C═.

In another embodiment, Z is N or —C═.

In another embodiment, m is 0 or 1.

In another embodiment, n is 0 or 1.

In another embodiment, p is 0 or 1.

In another embodiment, R¹ is selected from the group consisting of H, F,Cl, Br, I, —OR^(a), C₁₋₈alk, C₁₋₄haloalk, —C(═O)—O—R^(a),—C(═O)NR^(a)R^(a), —OR^(c), and —C(═O)NR^(a)R^(c).

In another embodiment, R¹ is selected from the group consisting of H, F,Cl, Br, —OR^(a), —C(═O)NR^(a)R^(a), —OR^(c), and —C(═O)NR^(a)R^(c).

In another embodiment, R¹ is selected from the group consisting of asaturated, partially-saturated or unsaturated 4-, 5-, 6-, or 7-memberedmonocyclic ring, wherein each said ring contains 0, 1, 2, or 3 N atomsand 0, 1, or 2 O atoms, and wherein each said ring is substituted by 0,1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a), —NR^(a)R^(a),—NR^(a)R^(c), R⁷, R⁸ and oxo.

In another embodiment, R¹ is selected from the group consisting of asaturated, partially-saturated or unsaturated 8-, 9-, 10-, 11-, or12-membered bicyclic ring, wherein each said ring contains 0, 1, 2, or 3N atoms and 0, 1, or 2 O atoms, and wherein each said ring issubstituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—NR^(a)R^(a), —NR^(a)R^(c), R⁷, R⁸ and oxo.

In another embodiment, R¹ is selected from the group consisting ofcyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl,azetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl,pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiopyranyl,oxaspiro[3.5]nonyl, azepanyl, oxepanyl, quinolinyl,dihydrotriazolo[4,3-a]pyrazinyl, pyrrolo[2,3-b]pyridinyl, all of whichare substituted by 0, 1, 2 or 3 groups selected from all of which aresubstituted by 0, 1 or 2 groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), CN, —C(═O)R^(b), —C(═O)OR^(a), —SR^(a), R⁷, andoxo.

In another embodiment, R¹ is -L-R⁷ wherein L is —CH₂—.

In another embodiment, R¹ is C₁₋₆alk substituted by 0, 1, 2 or 3 groupsselected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk,CN, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a), R⁸ and oxo.

In another embodiment, R¹ is selected from the group consisting of: Cl,Br, I, COOH,

In another embodiment, R¹ is selected from the group consisting of:

In another embodiment, R² is, independently in each instance, F, Cl, Br,CN, OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk.

In another embodiment, R³ is, independently in each instance, F, Cl, Br,CN, OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk.

In another embodiment, R⁴ is F.

In another embodiment, R⁵ is methyl.

In another embodiment, R⁶ is methyl.

In another embodiment, R⁷ is a saturated 3-, 4-, 5- or 6-memberedmonocyclic ring containing 0 or 1 N atom and 0 or 1 O atom, which issubstituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁸ and oxo.

In another embodiment, R⁸ is C₁₋₆alk substituted by 0 or 1 —OR^(a).

In another embodiment, R^(a) is H or C₁₋₆alk substituted by 0 or 1 —OH,—OC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk.

In another embodiment, R^(c) is a C₀₋₄alk-linked saturated,partially-saturated or unsaturated 3-, 5-, or 6-membered monocyclic ringcontaining 0 or 1 N atom and 0 or 1 atom selected from O and S, which issubstituted by 0 or 1 groups selected from F, C₁₋₆alk, C₁₋₄haloalk,—OR^(a), R⁷, or R⁸.

In another embodiment, the group of formula:

is selected from the group consisting of

In another embodiment, the group of formula:

is selected from the group consisting of

In another embodiment, the group of formula:

is selected from the group consisting of

Another aspect of the invention relates to a method of treatingconditions that may be treated with PDE10 inhibitors comprising the stepof administering a compound of formula (I) of the present invention.

Another aspect of the invention relates to a method wherein saidcondition that may be treated with PDE10 inhibitors is selected from thegroup consisting of psychoses, Parkinson's disease, dementias, obsessivecompulsive disorder, tardive dyskinesia, choreas, depression, mooddisorders, impulsivity, drug addiction, attention deficit/hyperactivitydisorder (ADHD), depression with parkinsonian states, personalitychanges with caudate or putamen disease, dementia and mania with caudateand pallidal diseases, and compulsions with pallidal disease.

Another aspect of the invention relates to a method wherein saidcondition that may be treated with PDE10 inhibitors is selected from thegroup consisting of schizophrenia, bipolar disorder, andobsessive-compulsive disorder.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound of formula (I) and a pharmaceutically-acceptablediluent or carrier.

Another aspect of the current invention relates to compounds having thegeneral structure of formula (II):

or any pharmaceutically-acceptable salt thereof, wherein:

Z is NH, NR⁶, S or O;

m is 0, 1, 2, 3 or 4;

n is 0, 1 or 2;

p is 0, 1 or 2;

y is 0, 1, 2, 3 or 4;

X¹ is N or C;

X⁵ is N or C;

Ring A is a carbon-linked-saturated, carbon-linked-partially-saturated,or carbon-linked-unsaturated 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing0 or 1 S or O atom; or a nitrogen-linked-saturated,nitrogen-linked-partially-saturated, or nitrogen-linked-unsaturated 4-,5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring heterocycle containingthe linking nitrogen and 0, 1 or 2 additional N atoms and containing 0or 1 S or O atom;

R² is, independently in each instance, F, Cl, Br, CN, OH, OC₁₋₄alk,C₁₋₄alk or C₁₋₄haloalk;

R³ is, independently in each instance, F, Cl, Br, CN, OH, OC₁₋₄alk,C₁₋₄alk or C₁₋₄haloalk;

R⁴ is independently in each instance, F, Cl, CH₃, CN, CF₃, CHF₂, CH₂F,OR^(a), or NR^(a)R^(a);

R⁵ is C₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), or R^(c);

R⁶ is C₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), or R^(c);

R⁷ is a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or7-membered monocyclic or 8-, 9-, 10-, 11-, or 12-membered bicyclic ringcontaining 0, 1, 2, 3, or 4 N atoms and 0 or 1 atoms selected from O andS, which is substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁸ and oxo;

R⁸ is a C₁₋₆alk substituted by 0, 1, 2 or 3 groups selected from F, Cl,Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo;

R⁹ is independently selected from the group consisting of H, F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—NR^(a)R^(c), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a), —NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a),—C₁₋₆ alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁷, R⁸ and oxo;

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk,—NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk; and

R^(c) is a C₀₋₄alk-linked saturated, partially-saturated or unsaturated3-, 4-, 5-, 6-, or 7-membered monocyclic or 8-, 9-, 10-, 11-, or12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1atom selected from O and S, which is substituted by 0, 1, 2 or 3 groupsselected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, R⁷, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo.

In another embodiment, Z is NH, N—C₁₋₄alk, or S.

Another aspect of the current invention relates to compounds having thegeneral structure of formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein m, n, p, y, R²,R³, R⁴, and R⁹ are as defined in compounds of formula (II), and anyother embodiments below.

In one embodiment of compounds of formula (IIa), ring A is bonded to thepyrazinyl ring via a carbon atom having an sp3 hybridization.

In one embodiment of compounds of formula (IIa), ring A is bonded to thepyrazinyl ring via a carbon atom having an sp2 hybridization.

In one embodiment of compounds of formula (IIa), ring A is bonded to thepyrazinyl ring via a carbon atom having an sp hybridization.

In one embodiment of compounds of formula (IIa), ring A is bonded to thepyrazinyl ring via a nitrogen atom having an sp3 hybridization.

In one embodiment of compounds of formula (IIa), ring A is bonded to thepyrazinyl ring via a nitrogen atom having an sp2 hybridization.

In another embodiment of compounds of formula (IIa), ring A is a5-membered ring saturated heterocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of compounds of formula (IIa), ring A is a6-membered ring saturated heterocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of compounds of formula (IIa), ring A is a4-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of compounds of formula (IIa), ring A is a5-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of compounds of formula (IIa), ring A is a6-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of compounds of formula (IIa), ring A is a7-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

Another aspect of the current invention relates to compounds having thegeneral structure of formula (IIb):

or a pharmaceutically acceptable salt thereof, wherein m, n, p, y, R²,R³, R⁴, and R⁹ are as defined in compounds of formula (II), and anyother embodiments below.

In one embodiment of compounds of formula (IIb), ring A is bonded to thepyrazinyl ring via a carbon atom having an sp3 hybridization.

In one embodiment of compounds of formula (IIb), ring A is bonded to thepyrazinyl ring via a carbon atom having an sp2 hybridization.

In one embodiment of compounds of formula (IIb), ring A is bonded to thepyrazinyl ring via a carbon atom having an sp hybridization.

In one embodiment of compounds of formula (IIb), ring A is bonded to thepyrazinyl ring via a nitrogen atom having an sp3 hybridization.

In one embodiment of compounds of formula (IIb), ring A is bonded to thepyrazinyl ring via a nitrogen atom having an sp2 hybridization.

In another embodiment of compounds of formula (IIb), ring A is a5-membered ring saturated heterocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of compounds of formula (IIb), ring A is a6-membered ring saturated heterocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of compounds of formula (IIb), ring A is a4-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of compounds of formula (IIb), ring A is a5-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of compounds of formula (IIb), ring A is a6-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆ alkN(R^(a))C(═O)R^(b), —C₁₋₆ alkOC(═O)R^(b), —C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of compounds of formula (IIb), ring A is a7-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment, the group of formula:

is selected from the group consisting of

In another embodiment, ring A is a carbon-linked-saturated,partially-saturated, or unsaturated 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing0 or 1 S or O atom.

In another embodiment, ring A is a carbon-linked-saturated 4-, 5-, 6-,7-, 8-, 9-, 10-, 11-, or 12-membered carbocycle ring containing 0, 1 or2 N atoms and containing 0 or 1 S or O atom.

In another embodiment, ring A is a nitrogen-linked-saturated 4-, 5-, 6-,7-membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0or 1 S or O atom.

In another embodiment, ring A is a nitrogen-linked-partially-saturated4-, 5-, 6-, 7-, 8-, 9-, 10-membered carbocycle ring containing 0, 1 or 2N atoms and containing 0 or 1 S or O atom.

In another embodiment, ring A is a nitrogen-linked-unsaturated 4-, 5-,6-, 8-, 10-, or 12-membered carbocycle ring containing 0, 1 or 2 N atomsand containing 0 or 1 S or O atom.

In another embodiment, ring A is selected from the group consisting ofcyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, and cycloheptyl.

In another embodiment, ring A is selected from the group consisting ofazetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl,pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydropyridinyl, and tetrahydrothiopyranyl.

In another embodiment, ring A is selected from the group consisting ofoxaspiro[3.5]nonyl, azepanyl, oxepanyl, and quinolinyl.

In another embodiment, ring A is selected from the group consisting ofcyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl,azetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl,pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiopyranyl,oxaspiro[3.5]nonyl, azepanyl, oxepanyl, quinolinyl,dihydrotriazolo[4,3-a]pyrazinyl, pyrrolo[2,3-b]pyridinyl, all of whichare substituted by 0, 1, 2 or 3 groups selected from all of which aresubstituted by 0, 1 or 2 groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), CN, —C(═O)R^(b), —C(═O)OR^(a), —SR^(a), R⁷, andoxo.

In another embodiment, ring A is selected from the group consisting of

In another embodiment, ring A is selected from the group consisting of:

In another embodiment, m is 0 or 1.

In another embodiment, n is 0 or 1.

In another embodiment, p is 0 or 1.

In another embodiment, y is 0, 1, 2, or 3.

In another embodiment, R⁹ is selected from the group consisting of H, F,Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —NR^(a)R^(a), —NR^(a)R^(c), R⁷, R⁸ and oxo.

In another embodiment, R² is, independently in each instance, F, Cl, Br,CN, OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk.

In another embodiment, R³ is, independently in each instance, F, Cl, Br,CN, OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk. In another embodiment, R⁴ isF.

In another embodiment, R⁶ is methyl.

In another embodiment, R⁷ is a saturated 5- or 6-membered monocyclicring containing 0 or 1 N atom and 0 or 1 O atom, which is substituted by0, 1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk,—OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁸ and oxo.

In another embodiment, R⁸ is C₁₋₆alk substituted by 0 or 1 —OR^(a).

In another embodiment, R^(a) is H or C₁₋₆alk substituted by 0 or 1 —OH,—OC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk.

In another embodiment, R^(c) is a C₀₋₄alk-linked saturated,partially-saturated or unsaturated 3-, 5-, or 6-membered monocyclic ringcontaining 0 or 1 N atom and 0 or 1 atom selected from O and S, which issubstituted by 0 or 1 groups selected from C₁₋₆alk, R⁷, or —OR^(a).

Another aspect of the invention relates to a method of treatingconditions that may be treated with PDE10 inhibitors comprising the stepof administering a compound of formula (II).

Another aspect of the invention relates to a method of treatingconditions that may be treated with PDE10 inhibitors comprising the stepof administering a compound of formula (II); wherein said condition isselected from the group consisting of psychoses, Parkinson's disease,dementias, obsessive compulsive disorder, tardive dyskinesia, choreas,depression, mood disorders, impulsivity, drug addiction, attentiondeficit/hyperactivity disorder (ADHD), depression with parkinsonianstates, personality changes with caudate or putamen disease, dementiaand mania with caudate and pallidal diseases, and compulsions withpallidal disease.

Another aspect of the invention relates to a method of treatingconditions that may be treated with PDE10 inhibitors comprising the stepof administering a compound of formula (II); wherein said condition isselected from the group consisting of schizophrenia, bipolar disorder,and obsessive-compulsive disorder.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound of formula (II) and a pharmaceutically-acceptablediluent or carrier.

Another aspect of the current invention relates to compounds having thegeneral structure of formula (III):

or any pharmaceutically-acceptable salt thereof, wherein:

Z is NH, NR⁶, S or O;

m is 0, 1, 2, 3 or 4;

n is 0, 1 or 2;

p is 0, 1 or 2;

y is 0, 1, 2, 3 or 4;

X¹ is N or C;

X⁵ is N or C;

Ring A is a carbon-linked-saturated, carbon-linked-partially-saturated,or carbon-linked-unsaturated 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing0 or 1 S or O atom; or a nitrogen-linked-saturated,nitrogen-linked-partially-saturated, or nitrogen-linked-unsaturated 4-,5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring heterocycle containingthe linking nitrogen and 0, 1 or 2 additional N atoms and containing 0or 1 S or O atom;

R² is, independently in each instance, F, Cl, Br, CN, OH, OC₁₋₄alk,C₁₋₄alk or C₁₋₄haloalk;

R³ is, independently in each instance, F, Cl, Br, CN, OH, OC₁₋₄alk,C₁₋₄alk or C₁₋₄haloalk;

R⁴ is independently in each instance, F, Cl, CH₃, CN, CF₃, CHF₂, CH₂F,OR^(a), or NR^(a)R^(a);

R⁵ is C₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), or R^(c);

R⁶ is C₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), or R^(c);

R⁷ is a saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or7-membered monocyclic or 8-, 9-, 10-, 11-, or 12-membered bicyclic ringcontaining 0, 1, 2, 3, or 4 N atoms and 0 or 1 atoms selected from O andS, which is substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁸ and oxo;

R⁸ is a C₁₋₆alk substituted by 0, 1, 2 or 3 groups selected from F, Cl,Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆ alkNR^(a)R^(a), —C₁₋₆ alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆ alkOC(═O)R^(b), —C₁₋₆alkC(═O)NR^(a)R^(a),—C₁₋₆alkC(═O)OR^(a) and oxo;

R⁹ is independently selected from the group consisting of H, F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—NR^(a)R^(c), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a), —NR^(a)C₂₋₆alkOR^(a), —C₁₋₆ alkNR^(a)R^(a),—C₁₋₆ alkOR^(a), —C₁₋₆ alkN(R^(a))C(═O)R^(b), —C₁₋₆ alkOC(═O)R^(b),C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁷, R⁸ and oxo;

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk,—NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk; and

R^(c) is a C₀₋₄alk-linked saturated, partially-saturated or unsaturated3-, 4-, 5-, 6-, or 7-membered monocyclic or 8-, 9-, 10-, 11-, or12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1atom selected from O and S, which is substituted by 0, 1, 2 or 3 groupsselected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, R⁷, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆ alkNR^(a)R^(a), —C₁₋₆alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b), —C₁₋₆alkC(═O)NR^(a)R^(a),—C₁₋₆alkC(═O)OR^(a) and oxo.

In another embodiment, Z is NH, N—C₁₋₄alk, or S.

Another aspect of the current invention relates to compounds having thegeneral structure of formula (IIIa):

or a pharmaceutically acceptable salt thereof, wherein m, n, p, y, R²,R³, R⁴, and R⁹ are as defined in compounds of formula (III), and anyother embodiments below.

In one embodiment of compounds of formula (IIIa), ring A is bonded tothe pyrazinyl ring via a carbon atom having an sp3 hybridization.

In one embodiment of compounds of formula (IIIa), ring A is bonded tothe pyrazinyl ring via a carbon atom having an sp2 hybridization.

In one embodiment of compounds of formula (IIIa), ring A is bonded tothe pyrazinyl ring via a carbon atom having an sp hybridization.

In one embodiment of compounds of formula (IIIa), ring A is bonded tothe pyrazinyl ring via a nitrogen atom having an sp3 hybridization.

In one embodiment of compounds of formula (IIIa), ring A is bonded tothe pyrazinyl ring via a nitrogen atom having an sp2 hybridization.

In another embodiment of compounds of formula (IIIa), ring A is a5-membered ring saturated heterocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment of compounds of formula (IIIa), ring A is a6-membered ring saturated heterocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment of compounds of formula (IIIa), ring A is a4-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment of compounds of formula (IIIa), ring A is a5-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment of compounds of formula (IIIa), ring A is a6-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment of compounds of formula (IIIa), ring A is a7-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

Another aspect of the current invention relates to compounds having thegeneral structure of formula (IIIb):

or a pharmaceutically acceptable salt thereof, wherein m, n, p, y, R²,R³, R⁴, and R⁹ are as defined in compounds of formula (III), and anyother embodiments below.

In one embodiment of compounds of formula (IIIb), ring A is bonded tothe pyrazinyl ring via a carbon atom having an sp3 hybridization.

In one embodiment of compounds of formula (IIIb), ring A is bonded tothe pyrazinyl ring via a carbon atom having an sp2 hybridization.

In one embodiment of compounds of formula (IIIb), ring A is bonded tothe pyrazinyl ring via a carbon atom having an sp hybridization.

In one embodiment of compounds of formula (IIIb), ring A is bonded tothe pyrazinyl ring via a nitrogen atom having an sp3 hybridization.

In one embodiment of compounds of formula (IIIb), ring A is bonded tothe pyrazinyl ring via a nitrogen atom having an sp2 hybridization.

In another embodiment of compounds of formula (IIIb), ring A is a5-membered ring saturated heterocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment of compounds of formula (IIIb), ring A is a6-membered ring saturated heterocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment of compounds of formula (IIIb), ring A is a4-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment of compounds of formula (IIIb), ring A is a5-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment of compounds of formula (IIIb), ring A is a6-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment of compounds of formula (IIIb), ring A is a7-membered ring saturated carbocycle, which is optionally substitutedwith —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), and oxo.

In another embodiment, the group of formula:

is selected from the group consisting of

In another embodiment, ring A is a carbon-linked-saturated,partially-saturated, or unsaturated 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing0 or 1 S or O atom.

In another embodiment, ring A is a carbon-linked-saturated 4-, 5-, 6-,7-, 8-, 9-, 10-, 11-, or 12-membered carbocycle ring containing 0, 1 or2 N atoms and containing 0 or 1 S or O atom.

In another embodiment, ring A is a nitrogen-linked-saturated 4-, 5-, 6-,7-membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0or 1 S or O atom.

In another embodiment, ring A is a nitrogen-linked-partially-saturated4-, 5-, 6-, 7-, 8-, 9-, 10-membered carbocycle ring containing 0, 1 or 2N atoms and containing 0 or 1 S or O atom.

In another embodiment, ring A is a nitrogen-linked-unsaturated 4-, 5-,6-, 8-, 10-, or 12-membered carbocycle ring containing 0, 1 or 2 N atomsand containing 0 or 1 S or O atom.

In another embodiment, ring A is selected from the group consisting ofcyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, and cycloheptyl.

In another embodiment, ring A is selected from the group consisting ofazetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl,pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydropyridinyl, and tetrahydrothiopyranyl.

In another embodiment, ring A is selected from the group consisting ofoxaspiro[3.5]nonyl, azepanyl, oxepanyl, and quinolinyl.

In another embodiment, ring A is selected from the group consisting ofcyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl,azetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl,pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiopyranyl,oxaspiro[3.5]nonyl, azepanyl, oxepanyl, quinolinyl, all of which aresubstituted by 0, 1, 2 or 3 groups selected from all of which aresubstituted by 0, 1 or 2 groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), CN, —C(═O)R^(b), —C(═O)OR^(a), —SR^(a), R⁷, andoxo.

In another embodiment, ring A is selected from the group consisting of:

In another embodiment, m is 0 or 1.

In another embodiment, n is 0 or 1.

In another embodiment, p is 0 or 1.

In another embodiment, y is 0, 1, 2, or 3.

In another embodiment, R⁹ is selected from the group consisting of H, F,Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —NR^(a)R^(a), —NR^(a)R^(c), R⁷, R⁸ and oxo.

In another embodiment, R² is, independently in each instance, F, Cl, Br,CN, OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk.

In another embodiment, R³ is, independently in each instance, F, Cl, Br,CN, OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk. In another embodiment, R⁴ isF.

In another embodiment, R⁶ is methyl.

In another embodiment, R⁷ is a saturated 5- or 6-membered monocyclicring containing 0 or 1 N atom and 0 or 1 O atom, which is substituted by0, 1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk,—OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁸ and oxo.

In another embodiment, R⁸ is C₁₋₆alk substituted by 0 or 1 —OR^(a).

In another embodiment, R^(a) is H or C₁₋₆alk substituted by 0 or 1 —OH,—OC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk.

In another embodiment, R^(c) is a C₀₋₄alk-linked saturated,partially-saturated or unsaturated 3-, 5-, or 6-membered monocyclic ringcontaining 0 or 1 N atom and 0 or 1 atom selected from O and S, which issubstituted by 0 or 1 groups selected from C₁₋₆alk, R⁷, or —OR^(a).

Another aspect of the invention relates to a method of treatingconditions that may be treated with PDE10 inhibitors comprising the stepof administering a compound of formula (III).

Another aspect of the invention relates to a method of treatingconditions that may be treated with PDE10 inhibitors comprising the stepof administering a compound of formula (III); wherein said condition isselected from the group consisting of psychoses, Parkinson's disease,dementias, obsessive compulsive disorder, tardive dyskinesia, choreas,depression, mood disorders, impulsivity, drug addiction, attentiondeficit/hyperactivity disorder (ADHD), depression with parkinsonianstates, personality changes with caudate or putamen disease, dementiaand mania with caudate and pallidal diseases, and compulsions withpallidal disease.

Another aspect of the invention relates to a method of treatingconditions that may be treated with PDE10 inhibitors comprising the stepof administering a compound of formula (III); wherein said condition isselected from the group consisting of schizophrenia, bipolar disorder,and obsessive-compulsive disorder.

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound of formula (III) and a pharmaceutically-acceptablediluent or carrier.

Another aspect of the current invention relates to compounds having thegeneral structure of formula (IV):

or any pharmaceutically-acceptable salt thereof, wherein:

X¹ is N or C;

X² is N or C;

X³ is N or C;

X⁴ is N or C; wherein no more than two of X¹, X², X³ and X⁴ are N;

Y is NH, NR⁵ or C(═O);

Z is NH, NR⁶, S or O;

m is 0, 1 or 2;

n is independently in each instance 0, 1 or 2;

R¹ is selected from H, F, Cl, Br, C₁₋₈alk, C₁₋₄haloalk, —OR^(a),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b) and —C(═O)NR^(a)R^(a), —C(═O)R^(d),—OR^(c), —NR^(a)R^(c), —N(R^(c))C(═O)R^(b), —N(R^(a))C(═O)R^(c) and—C(═O)NR^(a)R^(c); or R¹ is -L-R⁷, wherein L is CH₂, NH, N(C₁₋₄alk), O,S, S═O or S(═O)₂; and R⁷ is a saturated, partially-saturated orunsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic or 8-, 9-, 10-,11-, or 12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0or 1 atoms selected from O and S, which is substituted by 0, 1, 2 or 3groups selected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo;

R² is, independently in each instance, F, Cl, Br, CN, OH, OC₁₋₄alk,C₁₋₄alk or C₁₋₄haloalk;

R³ is, independently in each instance, F, Cl, Br, CN, OH, OC₁₋₄alk,C₁₋₄alk or C₁₋₄haloalk;

R⁴ is independently in each instance, F, Me or CN;

R⁵ is C₁₋₈alk, C₁₋₄haloalk, or —C(═O)R^(b);

R⁶ is C₁₋₈alk, C₁₋₄haloalk, or —C(═O)R^(b);

R^(a) is independently, at each instance, H or R^(b);

R^(b) is independently, at each instance, phenyl, benzyl or C₁₋₆alk, thephenyl, benzyl and C₁₋₆alk being substituted by 0, 1, 2 or 3substituents selected from halo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk, —NH₂,—NHC₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk;

R^(c) is a C₀₋₁alk-linked saturated, partially-saturated or unsaturated3-, 4-, 5-, 6-, or 7-membered monocyclic or 8-, 9-, 10-, 11-, or12-membered bicyclic ring containing 0, 1, 2 or 3 N atoms and 0 or 1atoms selected from O and S, which is substituted by 0, 1, 2 or 3 groupsselected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk,CN, —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆ alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo; and

R^(d) is a nitrogen-linked saturated, partially-saturated or unsaturated5-, 6- or 7-membered ring heterocycle containing the linking nitrogenand 0, 1 or 2 additional nitrogen atoms and containing 0 or 1 sulfur oroxygen atoms, the heterocycle being substituted by 0, 1, 2 or 3substituents selected from oxo, halo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk,—NH₂, —NHC₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk.

In another embodiment, Z is NH.

In another embodiment, Z is NR⁶.

In another embodiment, Z is S.

In another embodiment, Z is O.

In another embodiment, Y is NH.

In another embodiment, Y is NR⁵.

In another embodiment, Y is C(═O).

In another embodiment, X¹ is N.

In another embodiment, X² is N.

In another embodiment, X³ is N.

In another embodiment, X⁴ is N.

In another embodiment, X¹, X², X³ and X⁴ are all C.

In another embodiment, R¹ is C₃₋₄alk substituted by 0, 1, 2 or 3 groupsselected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk,CN, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a) and oxo.

In another embodiment, R¹ is selected from piperidine, piperazine,pyrrolidine, morpholine, pyridine and pyrimidine, all of which aresubstituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(b),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a) and oxo.

In another embodiment, R¹ is phenyl, all of which are substituted by 0,1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a) and oxo.

In another embodiment, R¹ is selected from piperidine, piperazine,pyrrolidine and morpholine, all of which are substituted by 0, 1, 2 or 3groups selected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆ alkNR^(a)R^(a), —C₁₋₆alkOR^(a) and oxo.

In another embodiment, R¹ is selected from pyridine and pyrimidine, eachof which are substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a) and oxo.

In another embodiment, R¹ is a saturated 5- or 6-membered carbocyclicring substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(b), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a) and oxo.

In another embodiment, R¹ is selected from

In another embodiment, m is 0.

In another embodiment, m is 1, and R⁴ is F.

In another embodiment, m is 2; and R⁴ is F.

In another embodiment, n is 0.

Another aspect of the invention relates to a method of treatingschizophrenia, bipolar disorder, or obsessive-compulsive disorder usingan effective amount of a compound of formula (IV).

Another aspect of the invention relates to a method of treating adisorder treatable by inhibition of PDE10 in a patient which methodcomprises administering to the patient a pharmaceutical compositioncomprising an effective amount of a compound of formula (IV).

Another aspect of the invention relates to a pharmaceutical compositioncomprising a compound of formula (IV) and a pharmaceutically-acceptablediluent or carrier.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments as a medicament.

Another aspect of the invention relates to the use of a compoundaccording to any of the above embodiments in the manufacture of amedicament for the treatment of schizophrenia, bipolar disorder, orobsessive-compulsive disorder.

Another aspect of the invention relates to compounds of selected fromthe group consisting of:

-   (1H-Benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone;-   (S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone;-   [4-(3-Chloro-pyrazin-2-yloxy)-phenyl]-(6-fluoro-1H-benzoimidazol-2-yl)-methanone;-   (1-Methyl-1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)-methanone;-   (1-Isopropyl-1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)-methanone;-   4-(3-(4-((1H-benzo[d]imidazol-2-yl)difluoromethyl)phenoxy)pyrazin-2-yl)morpholine-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-hydroxypiperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxypiperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-methoxypiperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (R)-(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2,6-dimethylmorpholino)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-methylpiperazin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperazin-1-yl)ethanone;-   1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-4-carbonitrile;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-ylamino)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-3-ylamino)pyrazin-2-yloxy)phenyl)methanone;-   (4-(3-(1,4-oxazepan-4-yl)pyrazin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-(methoxymethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-4-one;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-(2-hydroxyethyl)piperazin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   ethyl    2-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperazin-1-yl)acetate;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-methoxypiperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   8-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decan-1-one;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-morpholinopiperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxypyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methylpiperazin-2-one;-   (S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-(hydroxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrazin-2-yloxy)phenyl)methanone;-   (R)-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-(hydroxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-(2-hydroxyethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-3-carbonitrile;-   1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;-   ethyl    1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-4-carboxylate;-   methyl    1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carboxylate;-   ethyl    1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-3-carboxylate;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(3-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxypyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-(1-hydroxyethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-4-carboxylic    acid;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(3-(2-hydroxyethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-(hydroxymethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-6-methylpiperazin-2-one;-   (1H-imidazo[4,5-b]pyridin-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone;-   (4-(3-chloropyrazin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone;-   (4-(3-chloropyrazin-2-yloxy)phenyl)(7-fluoro-1H-benzo[d]imidazol-2-yl)methanone;-   (4-(3-chloropyrazin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxyazetidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;-   (S)-N-(4-(3-(2-(Methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(Tetrahydro-2H-pyran-3-ylamino)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   (S)-2-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-2-yl)propan-2-ol;-   1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-4-methylpiperidin-4-ol;-   Benzo[d]thiazol-2-yl(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone;-   N-(4-(3-Chloropyrazin-2-yloxy)phenyl)-6-fluorobenzo[d]thiazol-2-amine;-   N-(4-(3-morpholinopyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine;-   5-fluoro-N-(4-(3-morpholinopyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine;-   N-(4-(3-morpholinopyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   2-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)propan-2-ol;-   1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-ol;-   N-(4-(3-(pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-3-ol;-   1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-4-carbonitrile;-   1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperazin-1-yl)ethanone;-   N-(4-(3-(4-methylpiperazin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   2-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)-1,1,1-trifluoropropan-2-ol;-   N-(4-(3-(2,6-dimethylmorpholino)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-((3-(1,1-dioxido-4-thiomorpholinyl)-2-pyrazinyl)oxy)phenyl)-1,3-benzothiazol-2-amine;-   (S)-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-2-yl)methanol;-   N-(4-(3-(azetidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)azetidine-3-carboxylic    acid;-   2-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperazin-1-yl)ethanol;-   N-(4-(3-(6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-4-carboxamide;-   N-(4-(3-(2-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   methyl    1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)azetidine-3-carboxylate;-   1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;-   (R)-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-3-yl)methanol;-   2-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)ethanol;-   N-(4-(3-(4-(methoxymethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(3-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   (1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)methanol;-   4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperazin-2-one;-   4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-1-isopropylpiperazin-2-one;-   N-(4-(3-(4-methoxypiperidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)azetidine-3-carbonitrile;-   4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-6-methylpiperazin-2-one;-   1-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)ethanol;-   methyl    1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidine-3-carboxylate;-   (1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-2-yl)methanol;-   N-(4-(3-(3-(methoxymethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-chloropyrazin-2-yloxy)phenyl)-7-fluorobenzo[d]thiazol-2-amine;-   N-(4-(3-chloropyrazin-2-yloxy)phenyl)-6-fluorobenzo[d]thiazol-2-amine;-   N-(4-(3-chloropyrazin-2-yloxy)phenyl)-5-fluorobenzo[d]thiazol-2-amine;-   N-(4-(3-chloropyrazin-2-yloxy)-2-fluorophenyl)benzo[d]thiazol-2-amine;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(trifluoromethyl)pyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(4-methoxybenzyloxy)pyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyridin-2(1H)-one;    (1H-benzo[d]imidazol-2-yl)(4-(3-(2-methylpyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)benzonitrile;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-methylpyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(2-methylpyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2,6-dimethoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(3-methoxypyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxyphenyl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxyquinolin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(5-fluoro-2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (5-fluoro-1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(5-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxypyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(6-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)benzonitrile;-   methyl    4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)benzoate;-   4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)benzoic    acid;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(3-methoxyphenyl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(quinolin-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(quinolin-5-yl)pyrazin-2-yloxy)phenyl)methanone;-   (4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone;-   2-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-4,4-dimethylcyclohex-2-enone;-   1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone;-   (1-(2-fluoroethyl)-1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;-   N-(4-(3-(2-methylpyridin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enone;-   3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enol;-   N-(4-(3-(6-morpholinopyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(4-morpholinophenyl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(6-methylpyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   5-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)picolinonitrile-   N-(4-(3-(pyrimidin-5-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(2-methoxypyrimidin-5-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(6-chloropyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   (5-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyridin-2-yl)methanol;-   N-(4-(3-(quinolin-5-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(pyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(3-methoxypyridin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(3-methoxyphenyl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   7-fluoro-N-(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(2-methoxypyridin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   6-fluoro-N-(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   5-fluoro-N-(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(5-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(2-fluoro-4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(2-fluoro-4-(3-(2-fluoropyridin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   tert-butyl    4-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate;-   (1H-benzo[d]imidazol-2-yl)(4-(3-methoxypyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-isopropoxypyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-isobutoxypyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(cyclopropylmethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2,2,2-trifluoroethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxyethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-2-ylmethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-phenoxypyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-3-yloxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(but-2-ynyloxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(4-methylthiazol-5-yl)ethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-((tetrahydrofuran-3-yl)methoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-morpholinoethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(pyrrolidin-1-yl)ethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(dimethylamino)ethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(1-methylpyrrolidin-2-yl)ethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-4-ylmethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(pyridin-2-yl)ethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(3-(pyridin-3-yl)propoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-3-ylmethoxy)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-propoxypyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-imidazo[4,5-b]pyridin-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   (6-fluoro-1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;

(1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;

-   (6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   (5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   1H-benzimidazol-2-yl(4-((3-(tetrahydro-2H-pyran-3-yl)-2-pyrazinyl)oxy)-phenyl)methanone;-   1H-Benzimidazol-2-yl(4-((3-(4-methoxy-1-cyclohexen-1-yl)-2-pyrazinyl)    oxy)phenyl)methanone;-   1H-benzimidazol-2-yl(4-((3-(cis-4-hydroxycyclohexyl)-2-pyrazinyl)oxy)phenyl)methanone;    and    1H-benzimidazol-2-yl(4-((3-(trans-4-hydroxycyclohexyl)-2-pyrazinyl)oxy)phenyl)methanone;-   cis-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;-   trans-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;-   cis-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;-   trans-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;-   N-(4-(3-(Tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanone;-   4-(2-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cyclohexanone;-   (1H-Benzo[d]imidazol-2-yl)(4-(3-((1s,4s)-4-hydroxy-4-methylcyclohexyl)pyridin-2-yloxy)phenyl)methanone;-   (1H-Benzo[d]imidazol-2-yl)(4-(3-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyridin-2-yloxy)phenyl)methanone;-   (1H-Benzo[d]imidazol-2-yl)(4-(3-(oxepan-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4,4-difluorocyclohex-1-enyl)pyrazin-2-yloxy)phenyl)methanone;-   4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)tetrahydro-2H-pyran-4-carbonitrile;-   N-methyl-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)tetrahydro-2H-pyran-4-ol;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-fluorotetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   N-(4-(3-(4-fluorotetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   1-tert-butyl 4-methyl    4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1,4-dicarboxylate;-   tert-butyl    4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-4-(hydroxymethyl)piperidine-1-carboxylate;-   N-(4-(3-(Tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine;-   N-(4-(3-(Tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   7-Methoxy-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine;-   3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)cyclohexanone;-   4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)tetrahydro-2H-pyran-4-carbonitrile;-   methyl    4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)tetrahydro-2H-pyran-4-carboxylate;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(4-hydroxytetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   6-fluoro-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(2-fluoro-4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(2-fluoro-4-(pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   7-fluoro-N-(4-(pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   5-fluoro-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   5-fluoro-N-(4-(pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   (1H-benzo[d]imidazol-2-yl)(4-(3-cyclopentylpyrazin-2-yloxy)phenyl)methanone;-   N-(4-(3-(tetrahydrofuran-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   1H-benzo[d]imidazole-2-yl(4-(3-(tetrahydro-2H-thiopyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   N-(4-(3-cyclopentylpyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;-   1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(1-(2-fluoroethyl)piperidin-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   methyl    4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate;-   1-(4-(3-(4-((1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanol;-   (1H-benzo[d]imidazol-2-yl)(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)methanone;-   1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)perdeuteroethanone;-   1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-methoxyethanone;-   1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-methoxyethanone;-   1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;-   1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;-   N-(4-(3-(1-(2-fluoroethyl)piperidin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   N-(4-(3-(1-methylpiperidin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;-   1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-1-oxopropan-2-yl    acetate;-   1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one;-   1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidin-1-yl)ethanone;-   1-(3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-1-yl)ethanone;-   1-(4-(3-(4-(1-methyl-1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;-   2-methoxy-1-(4-(3-(4-(1-methyl-1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;-   2-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-oxoethyl    acetate;-   1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-(dimethylamino)ethanone;-   1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-(dimethylamino)ethanone;-   3-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-3-oxopropanenitrile;-   1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)-2-fluorophenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;-   1-(4-(3-(6-(benzo[d]thiazol-2-ylamino)pyridin-3-yloxy)pyrazin-2-yl)piperidin-1-yl)ethanone;-   1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidin-1-yl)ethanone;-   1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;-   4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methyl-5,6-dihydropyridin-2(1H)-one;-   4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methylpiperidin-2-one;-   3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-phenethylpyrazine-2-carboxamide;-   3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(4-(trifluoromethyl)phenethyl)pyrazine-2-carboxamide;-   (S)-3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(1-methoxypropan-2-yl)pyrazine-2-carboxamide;-   3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(2-(pyridin-2-yl)ethyl)pyrazine-2-carboxamide;-   3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(2-hydroxyethyl)pyrazine-2-carboxamide;-   3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(1-(pyridin-2-yl)propan-2-yl)pyrazine-2-carboxamide;-   3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(1-benzylcyclopropyl)pyrazine-2-carboxamide;-   (R)-1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;-   (S)-1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;-   (R)-ethyl    1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-3-carboxylate;-   (S)-ethyl    1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-3-carboxylate;-   (S)-methyl    1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carboxylate;-   (R)-methyl    1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carboxylate;-   (R)-4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-6-methylpiperazin-2-one;-   (S)-4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-6-methylpiperazin-2-one;-   (1H-benzo[d]imidazol-2-yl)(4-(3-((1R,3S)-3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-((1S,3R)-3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;-   (1S,3R)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;-   (1R,3S)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;-   (1H-benzo[d]imidazol-2-yl)(4-(3-((1S,3S)-3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;-   (1H-benzo[d]imidazol-2-yl)(4-(3-((1R,3R)-3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;-   (1S,3S)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;-   (1R,3R)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;-   (R)-1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;-   (S)-1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;-   (R)-1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;-   (S)-1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;-   (R)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanone;-   (S)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanone;    or

any pharmaceutically-acceptable salt thereof.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, partially racemicmixtures and separate enantiomers and diasteromers.

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of the present invention wherein one ormore atoms are replaced by atoms having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberwhich predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include, but are not limited to, isotopes of hydrogen, such as²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁸Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of the present invention, forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of the present invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Preparations using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Specific embodiments of the present invention include the compoundsexemplified in the Examples below and their pharmaceutically acceptablesalts, complexes, solvates, polymorphs, stereoisomers, metabolites,prodrugs, and other derivatives thereof, Unless otherwise specified, thefollowing definitions apply to terms found in the specification andclaims:

“C_(α-β)alk” means an alkyl group comprising a minimum of α and amaximum of β carbon atoms in a branched, cyclical or linear relationshipor any combination of the three, wherein α and β represent integers. Thealkyl groups described in this section may also contain one or twodouble or triple bonds. A designation of C₀alk indicates a direct bond.Examples of C₁₋₆alkyl include, but are not limited to the following:

“Benzo group”, alone or in combination, means the divalent radicalC₄H₄═, one representation of which is —CH═CH—CH═CH—, that when vicinallyattached to another ring forms a benzene-like ring—for exampletetrahydronaphthylene, indole and the like.

The terms “oxo” and “thioxo” represent the groups ═O (as in carbonyl)and ═S (as in thiocarbonyl), respectively.

“Halo” or “halogen” means a halogen atoms selected from F, Cl, Br and I.

“C_(α-β)haloalk” means an alk group, as described above, wherein anynumber—at least one—of the hydrogen atoms attached to the alk chain arereplaced by F, Cl, Br or I.

The group N(R^(a))R^(a) and the like include substituents where the twoR^(a) groups together form a ring, optionally including a N, O or Satom, and include groups such as:

The group N(C_(α-β)alk) C_(α-β)alk, wherein α and β are as definedabove, include substituents where the two C_(α-β)alk groups togetherform a ring, optionally including a N, O or S atom, and include groupssuch as:

“Carbocycle” means a ring comprising by itself or in combination withother terms, represents, unless otherwise stated, cyclic version of“C_(α-β)alk”. Thus, the term “carbocycle” is meant to be included in theterms “C_(α-β)alk”. Examples of carbocycle include cyclopentyl,cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene,cyclohexylene and the like.

“Heterocycle” means a ring comprising at least one carbon atom and atleast one other atom selected from N, O and S. Examples of heterocyclesthat may be found in the claims include, but are not limited to, thefollowing:

“Pharmaceutically-acceptable salt” means a salt prepared by conventionalmeans, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” see infra and Berge et al., J.Pharm. Sci. 66:1 (1977).

“Saturated, partially-saturated or unsaturated” includes substituentssaturated with hydrogens, substituents completely unsaturated withhydrogens and substituents partially saturated with hydrogens.

“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl,phthaloyl and the like. A mixture of protecting groups can be used toprotect the same amino group, such as a primary amino group can beprotected by both an aralkyl group and an aralkoxycarbonyl group. Aminoprotecting groups can also form a heterocyclic ring with the nitrogen towhich they are attached, for example, 1,2-bis(methylene)benzene,phthalimidyl, succinimidyl, maleimidyl and the like and where theseheterocyclic groups can further include adjoining aryl and cycloalkylrings. In addition, the heterocyclic groups can be mono-, di- ortri-substituted, such as nitrophthalimidyl. Amino groups may also beprotected against undesired reactions, such as oxidation, through theformation of an addition salt, such as hydrochloride, toluenesulfonicacid, trifluoroacetic acid and the like. Many of the amino protectinggroups are also suitable for protecting carboxy, hydroxy and mercaptogroups. For example, aralkyl groups. Alkyl groups are also suitablegroups for protecting hydroxy and mercapto groups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-trisilyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium fluoride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted heteroaryl groups (Y′═O, S,NR), and the like, which are illustrated in the following examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The specification and claims contain listing of species using thelanguage “selected from . . . and . . . ” and “is . . . or . . . ”(sometimes referred to as Markush groups). When this language is used inthis application, unless otherwise stated it is meant to include thegroup as a whole, or any single members thereof, or any subgroupsthereof. The use of this language is merely for shorthand purposes andis not meant in any way to limit the removal of individual elements orsubgroups as needed.

Utility and Methods of Use

Provided herein are methods for treating a disorder or disease byinhibiting PDE10 enzyme. The methods, in general, comprises the step ofadministering a therapeutically effective amount of a compounds of thepresent invention, or an individual stereoisomer, a mixture ofstereoisomers, or a pharmaceutically acceptable salt or solvate thereof,to a patient in need thereof to treat the disorder or disease.

In certain embodiments, this invention provides a use of a compound asdescribed herein in the manufacture of a medicament for treating adisorder or disease treatable by inhibition of PDE10.

The compounds of the present invention inhibit PDE10 enzyme activity,and hence raise the levels of cAMP or cGMP within cells that expressPDE10. Accordingly, inhibition of PDE10 enzyme activity would be usefulin the treatment of diseases caused by deficient amounts of cAMP or cGMPin cells. PDE10 inhibitors would also be of benefit in cases whereinraising the amount of cAMP or cGMP above normal levels results in atherapeutic effect. Inhibitors of PDE10 may be used to treat disordersof the peripheral and central nervous system, cardiovascular diseases,cancer, gastro-enterological diseases, endocrinological diseases andurological diseases.

Indications that may be treated with PDE10 inhibitors, either alone orin combination with other drugs, include, but are not limited to, thosediseases thought to be mediated in part by the basal ganglia, prefrontalcortex, and hippocampus. These indications include psychoses,Parkinson's disease, dementias, obsessive compulsive disorder, tardivedyskinesia, choreas, depression, mood disorders, impulsivity, drugaddiction, attention deficit/hyperactivity disorder (ADHD), depressionwith parkinsonian states, personality changes with caudate or putamendisease, dementia and mania with caudate and pallidal diseases, andcompulsions with pallidal disease.

Psychoses are disorders that affect an individual's perception ofreality. Psychoses are characterized by delusions and hallucinations.The compounds of the present invention are suitable for use in treatingpatients suffering from all forms of psychoses, including, but notlimited to, schizophrenia, late-onset schizophrenia, schizoaffectivedisorders, prodromal schizophrenia, and bipolar disorders. Treatment canbe for the positive symptoms of schizophrenia as well as for thecognitive deficits and negative symptoms. Other indications for PDE10inhibitors include psychoses resulting from drug abuse (includingamphetamines and PCP), encephalitis, alcoholism, epilepsy, Lupus,sarcoidosis, brain tumors, multiple sclerosis, dementia with Lewybodies, or hypoglycemia. Other psychiatric disorders, like posttraumaticstress disorder (PTSD), and schizoid personality can also be treatedwith PDE10 inhibitors.

Obsessive-compulsive disorder (OCD) has been linked to deficits in thefrontal-striatal neuronal pathways (Saxena et al., Br. J. PsychiatrySuppl, 35:26-37, 1998). Neurons in these pathways project to striatalneurons that express PDE10. PDE10 inhibitors cause cAMP to be elevatedin these neurons; elevations in cAMP result in an increase in CREBphosphorylation and thereby improve the functional state of theseneurons. The compounds of the present invention are therefore suitablefor use in the indication of OCD. OCD may result, in some cases, fromstreptococcal infections that cause autoimmune reactions in the basalganglia (Giedd et al., Am J Psychiatry. 157:281-283, 2000). BecausePDE10 inhibitors may serve a neuroprotective role, administration ofPDE10 inhibitors may prevent the damage to the basal ganglia afterrepeated streptococcal infections and thereby prevent the development ofOCD.

In the brain, the level of cAMP or cGMP within neurons is believed to berelated to the quality of memory, especially long term memory. Withoutwishing to be bound to any particular mechanism, it is proposed that,since PDE10 degrades cAMP or cGMP, the level of this enzyme affectsmemory in animals, for example, in humans. A compound that inhibits cAMPphosphodiesterase (PDE) can thereby increase intracellular levels ofcAMP, which in turn activate a protein kinase that phosphorylates atranscription factor (cAMP response binding protein). The phosphorylatedtranscription factor then binds to a DNA promoter sequence to activategenes that are important in long term memory. The more active such genesare, the better is long-term memory. Thus, by inhibiting aphosphodiesterase, long term memory can be enhanced.

Dementias are diseases that include memory loss and additionalintellectual impairment separate from memory. The compounds of thepresent invention are suitable for use in treating patients sufferingfrom memory impairment in all forms of dementia. Dementias areclassified according to their cause and include: neurodegenerativedementias (e.g., Alzheimer's, Parkinson's disease, Huntington's disease,Pick's disease), vascular (e.g., infarcts, hemorrhage, cardiacdisorders), mixed vascular and Alzheimer's, bacterial meningitis,Creutzfeld-Jacob Disease, multiple sclerosis, traumatic (e.g., subduralhematoma or traumatic brain injury), infectious (e.g., HIV), genetic(down syndrome), toxic (e.g., heavy metals, alcohol, some medications),metabolic (e.g., vitamin B12 or folate deficiency), CNS hypoxia,Cushing's disease, psychiatric (e.g., depression and schizophrenia), andhydrocephalus.

The condition of memory impairment is manifested by impairment of theability to learn new information and/or the inability to recallpreviously learned information. The present invention includes methodsfor dealing with memory loss separate from dementia, including mildcognitive impairment (MCI) and age-related cognitive decline. Thepresent invention includes methods of treatment for memory impairment asa result of disease. Memory impairment is a primary symptom of dementiaand can also be a symptom associated with such diseases as Alzheimer'sdisease, schizophrenia, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease,and head trauma as well as age-related cognitive decline. The compoundsof the present invention are suitable for use in the treatment of memoryimpairment due to, for example, Alzheimer's disease, multiple sclerosis,amylolaterosclerosis (ALS), multiple systems atrophy (MSA),schizophrenia, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeld-Jakob disease, depression, aging, head trauma,stroke, spinal cord injury, CNS hypoxia, cerebral senility, diabetesassociated cognitive impairment, memory deficits from early exposure ofanesthetic agents, multiinfarct dementia and other neurologicalconditions including acute neuronal diseases, as well as HIV andcardiovascular diseases.

The compounds of the present invention are also suitable for use in thetreatment of a class of disorders known as polyglutamine-repeatdiseases. These diseases share a common pathogenic mutation. Theexpansion of a CAG repeat, which encodes the amino acid glutamine,within the genome leads to production of a mutant protein having anexpanded polyglutamine region. For example, Huntington's disease hasbeen linked to a mutation of the protein huntingtin. In individuals whodo not have Huntington's disease, huntingtin has a polyglutamine regioncontaining about 8 to 31 glutamine residues. For individuals who haveHuntington's disease, huntingtin has a polyglutamine region with over 37glutamine residues. Aside from Huntington's disease (HD), other knownpolyglutamine-repeat diseases and the associated proteins includedentatorubral-pallidoluysian atrophy, DRPLA (atrophin-1);spinocerebellar ataxia type-1 (ataxin-1); spinocerebellar ataxia type-2(ataxin-2); spinocerebellar ataxia type-3 (also called Machado-Josephdisease or MJD) (ataxin-3); spinocerebellar ataxia type-6 (alpha1a-voltage dependent calcium channel); spinocerebellar ataxia type-7(ataxin-7); and spinal and bulbar muscular atrophy (SBMA, also know asKennedy disease).

The basal ganglia are important for regulating the function of motorneurons; disorders of the basal ganglia result in movement disorders.Most prominent among the movement disorders related to basal gangliafunction is Parkinson's disease (Obeso et al., Neurology. 62(1 Suppl1):S17-30, 2004). Other movement disorders related to dysfunction of thebasal ganglia include tardive dyskinesia, progressive supranuclear palsyand cerebral palsy, corticobasal degeneration, multiple system atrophy,Wilson disease, dystonia, tics, and chorea. The compounds of theinvention are also suitable for use to treat movement disorders relatedto dysfunction of basal ganglia neurons.

PDE10 inhibitors are useful in raising cAMP or cGMP levels and preventneurons from undergoing apoptosis. PDE10 inhibitors may beanti-inflammatory by raising cAMP in glial cells. The combination ofanti-apoptotic and anti-inflammatory properties, as well as positiveeffects on synaptic plasticity and neurogenesis, make these compoundsuseful to treat neurodegeneration resulting from any disease or injury,including stroke, spinal cord injury, Alzheimer's disease, multiplesclerosis, amylolaterosclerosis (ALS), and multiple systems atrophy(MSA).

Autoimmune diseases or infectious diseases that affect the basal gangliamay result in disorders of the basal ganglia including ADHD, OCD, tics,Tourette's disease, Sydenham chorea. In addition, any insult to thebrain can potentially damage the basal ganglia including strokes,metabolic abnormalities, liver disease, multiple sclerosis, infections,tumors, drug overdoses or side effects, and head trauma. Accordingly,the compounds of the invention can be used to stop disease progressionor restore damaged circuits in the brain by a combination of effectsincluding increased synaptic plasticity, neurogenesis,anti-inflammatory, nerve cell regeneration and decreased apoptosis.

The growth of some cancer cells is inhibited by cAMP and cGMP. Upontransformation, cells may become cancerous by expressing PDE10 andreducing the amount of cAMP or cGMP within cells. In these types ofcancer cells, inhibition of PDE10 activity inhibits cell growth byraising cAMP. In some cases, PDE10 may be expressed in the transformed,cancerous cell but not in the parent cell line. In transformed renalcarcinoma cells, PDE10 is expressed and PDE10 inhibitors reduce thegrowth rate of the cells in culture. Similarly, breast cancer cells areinhibited by administration of PDE10 inhibitors. Many other types ofcancer cells may also be sensitive to growth arrest by inhibition ofPDE10. Therefore, compounds disclosed in this invention can be used tostop the growth of cancer cells that express PDE10.

The compounds of the invention are also suitable for use in thetreatment of diabetes and related disorders such as obesity, by focusingon regulation of the cAMP signaling system. By inhibiting PDE-10,especially PDE-10A, intracellular levels of cAMP are increased, therebyincreasing the release of insulin-containing secretory granules and,therefore, increasing insulin secretion. See, for example, WO2005/012485, which is hereby incorporated by reference in its entirety.The compounds of Formula (I) can also be used to treat diseasesdisclosed in US Patent application publication No. 2006/019975, thedisclosure of which is incorporated herein by reference in its entirety.

Testing

The PDE10 inhibitory activities of the compounds of the presentinvention can be tested, for example, using the in vitro and in vivoassays described in the Biological Examples below.

Administration and Pharmaceutical Compositions

In general, the compounds of this invention can be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of a compound of this invention, i.e., the active ingredient,depends upon numerous factors, such as the severity of the disease to betreated, the age and relative health of the subject, the potency of thecompound used, the route and form of administration, and other factors.

Therapeutically effective amounts of compounds of formula (I) may rangefrom approximately 0.1-1000 mg per day; preferably 0.5 to 250 mg/day,more preferably 3.5 mg to 70 mg per day.

In general, compounds of this invention can be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors, such as the modeof drug administration (e.g., for oral administration, formulations inthe form of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area, i.e., decreasing particlesize. For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of, in general, a compounds of thepresent invention in combination with at least one pharmaceuticallyacceptable excipient. Acceptable excipients are non-toxic, aidadministration, and do not adversely affect the therapeutic benefit ofthe compounds of the present invention. Such excipient may be any solid,liquid, semi-solid or, in the case of an aerosol composition, gaseousexcipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, Gennaro, A. R. (MackPublishing Company, 18th ed., 1995).

The level of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationcontains, on a weight percent (wt %) basis, from about 0.01-99.99 wt %of a compounds of the present invention based on the total formulation,with the balance being one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 1-80 wt %.

The compounds can be administered as the sole active agent or incombination with other pharmaceutical agents such as other agents usedin the treatment of psychoses, especially schizophrenia and bipolardisorder, obsessive-compulsive disorder, Parkinson's disease,Alzheimer's disease, cognitive impairment and/or memory loss, e.g.,nicotinic α-7 agonists, PDE4 inhibitors, other PDE10 inhibitors, calciumchannel blockers, muscarinic m1 and m2 modulators, adenosine receptormodulators, ampakines, NMDA-R modulators, mGluR modulators, dopaminemodulators, serotonin modulators, canabinoid modulators, andcholinesterase inhibitors (e.g., donepezil, rivastigimine, andgalanthanamine). In such combinations, each active ingredient can beadministered either in accordance with their usual dosage range or adose below their usual dosage range, and can be administered eithersimultaneously or sequentially.

Drugs suitable in combination with the compounds of the presentinvention include, but are not limited to, other suitable schizophreniadrugs such as Clozaril, Zyprexa, Risperidone, and Seroquel; bipolardisorder drugs, including, but not limited to, Lithium, Zyprexa, andDepakote; Parkinson's disease drugs, including, but not limited to,Levodopa, Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane,and Cogentin; agents used in the treatment of Alzheimer's disease,including, but not limited to, Reminyl, Cognex, Aricept, Exelon,Akatinol, Neotropin, Eldepryl, Estrogen and Cliquinol; agents used inthe treatment of dementia, including, but not limited to, Thioridazine,Haloperidol, Risperidone, Cognex, Aricept, and Exelon; agents used inthe treatment of epilepsy, including, but not limited to, Dilantin,Luminol, Tegretol, Depakote, Depakene, Zarontin, Neurontin, Barbita,Solfeton, and Felbatol; agents used in the treatment of multiplesclerosis, including, but not limited to, Detrol, Ditropan XL,OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and Copaxone;agents used in the treatment of Huntington's disease, including, but notlimited to, Amitriptyline, Imipramine, Despiramine, Nortriptyline,Paroxetine, Fluoxetine, Setraline, Terabenazine, Haloperidol,Chloropromazine, Thioridazine, Sulpride, Quetiapine, Clozapine, andRisperidone; agents useful in the treatment of diabetes, including, butnot limited to, PPAR ligands (e.g. agonists, antagonists, such asRosiglitazone, Troglitazone and Pioglitazone), insulin secretagogues(e.g., sulfonylurea drugs, such as Glyburide, Glimepiride,Chlorpropamide, Tolbutamide, and Glipizide, and non-sulfonylsecretagogues), α-glucosidase inhibitors (such as Acarbose, Miglitol,and Voglibose), insulin sensitizers (such as the PPAR-γ agonists, e.g.,the glitazones; biguanides, PTP-1B inhibitors, DPP-IV inhibitors, and11beta-HSD inhibitors), hepatic glucose output lowering compounds (suchas glucagon antagonists and metaformin, e.g., Glucophage and GlucophageXR), insulin and insulin derivatives (both long and short acting formsand formulations of insulin); and anti-obesity drugs, including, but notlimited to, β-3 agonists, CB-1 agonists, neuropeptide Y5 inhibitors,Ciliary Neurotrophic Factor and derivatives (e.g., Axokine), appetitesuppressants (e.g., Sibutramine), and lipase inhibitors (e.g.,Orlistat).

EXPERIMENTAL

In the following schemes, the compounds of the invention, along withtheir definitions, such as m, n, p, R¹, R², R³, R⁴, X¹, X², X³, X⁴, X⁵,X⁶, X⁷, X⁸, X⁹, X¹⁰, X¹¹, Y and Z, are as described above.

Unless otherwise noted, all materials were obtained from commercialsuppliers and used without further purification. All parts are by weightand temperatures are in degrees centigrade unless otherwise indicated.All microwave assisted reactions were conducted with a SmithSynthesizer™ from Biotage™. All compounds showed NMR spectra consistentwith their assigned structures. Melting points were determined on aBuchi apparatus and are uncorrected. Mass spectral data was determinedby electrospray ionization technique. All examples were purified to >90%purity as determined by high-performance liquid chromatography. Unlessotherwise stated, reactions were run at room temperature.

The following abbreviations are used:

DCM—dichloromethaneDMSO—dimethyl sulfoxide

DMF—N,N-dimethylformamide

THF—tetrahydrofuranEt₂O—diethyl etherEtOAc—ethyl acetateMeOH—methyl alcoholEtOH—ethyl alcoholIPA—isopropyl alcoholMe—methylMeCN—acetonitrileMeI—iodomethaneNMP—1-methyl-2-pyrrolidinoneDCM—dichloromethaneTFA—trifluoroacetic acidMTBE—methyl tert-butyl etherDIPEA—diisopropylethyl amineHBTU—2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphateHATU—O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphateSat.—saturatedh—hourmin—minutesmL—millilitersg—gramsmg—milligrams(rac)—racemic mixture of enantiomers(±)—racemic mixture of enantiomers

All compounds were divided in five classes based on their IC50 valuesagainst PDE10. The range of the IC50 in each class is as follows:

“+” designates an IC₅₀ value in the range beginning from 1.0 uM andending at 5.0 uM;“++” designates an IC₅₀ value in the range beginning from 250 nM andending at 1.0 uM;“+++” designates an IC₅₀ value in the range beginning from 100 nM andending at 250 nM;“++++” designates an IC₅₀ value in the range beginning from 25 nM andending at 100 nM; and“+++++” designates an IC₅₀ value of less than 25 nM.

Example 1(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-MORPHOLINOPYRAZIN-2-YLOXY)-PHENYL)METHANONE

STEP 1. ETHYL 4-(3-CHLOROPYRAZIN-2-YLOXY)BENZOATE

To a solution of 4-hydroxybenzoic acid ethyl ester (55.21 g, 332.3 mmol)and 2,3-dichloropyrazine (49.50 g, 332.3 mmol) in DMSO (300 mL) wasadded cesium carbonate (129.9 g, 398.7 mmol). The mixture was heated to70° C. until the starting material was consumed. The mixture was cooledto RT, diluted with water and DCM, the layers were separated and theaqueous layer was extracted with DCM (2×). The combined organics werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude material was washed with copious amounts of methanol and dried togive ethyl 4-(3-chloropyrazin-2-yloxy)benzoate.

STEP 2.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-CHLOROPYRAZIN-2-YLOXY)PHENYL)-METHANONE

A solution of benzene-1,2-diamine (1.5 g, 14 mmol), triethylorthoformate (5.7 mL, 37 mmol), and benzenesulfonic acid (0.075 g, 0.47mmol) in toluene (15 mL) was heated to reflux for 4 h and then slowlydistilled to remove half of the solvent. The mixture was then cooled toRT and neutralized with diisopropyl amine, followed by addition of asolution of ethyl 4-(3-chloropyrazin-2-yloxy)benzoate (4.3 g, 15 mmol)in THF (15 mL). The mixture was cooled to −78° C. and 1.2 equiv of LDA(9.2 mL, 17 mmol) was added. After aging at −78° C. for 1.5 h, themixture was warmed to RT after 1.5 h and then 2N HCl was added and themixture was agitated for 30 min. Following that, the mixture wasadjusted to pH 9 with 1N NaOH. Ethyl acetate was added and the layerswere separated, the aqueous was extracted with ethyl acetate (3×), andthe combined organics were washed with brine, dried over Na₂SO₄,filtered and concentrated. Upon treatment with MeOH, a yellow solidcrashed out which was filtered and collected to give(1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone.

STEP 3.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-MORPHOLINOPYRAZIN-2-YLOXY)-PHENYL)METHANONE

A solution of(1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)-methanone(23.00 g, 65.6 mmol) and morpholine (17.2 mL, 197 mmol) was heated to90° C. in DMSO (165 mL). After complete consumption of the startingmaterial, the hot solution was dripped into ice water which caused ayellow solid to precipitate. The solid was slurried in boiling EtOH (600mL) and enough tetrahydrofuran was added to completely dissolve thesolids. The solution was transferred to the freezer for crystallization.The solid was collected by filtration and air-dried to give(1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone.MS (ESI, pos. ion) m/z: 402.1 (M+1). IC50 (uM) ++++.

Example 2(S)-(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(4-(1,1,1-TRIFLUORO-2-HYDROXYPROPAN-2-YL)PIPERIDIN-1-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1. N-METHOXY-N-METHYLPIPERIDINE-4-CARBOXAMIDE

To a mixture of piperidine-4-carboxylic acid (100 g, 775 mmol) in1,4-dioxane (400 mL) and water (100 mL), triethylamine (135 mL, 969mmol) was added at 25-30° C. and stirred for 15 min. Then 110 g of bocanhydride was added. It was stirred for overnight at the sametemperature. After completion of the reaction, the solvent was removedunder vacuum. The residue was purified by dilution with EtOAc andwashing with H₂O (1000 mL). The organic layer was dried over anhydroussodium sulfate and concentrated under vacuum to afford1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid product.

To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (50g, 218 mmol) in DCM (500 mL), 1,1-carbonyldiimidazole (46 g, 284 mmol)was added and the reaction mixture was stirred for 1 h at 25-30° C.N,O-Dimethylamine hydrochloride (30 g, 306 mmol) was then added and theresulting mixture was stirred for 15 h at 25-30° C. After completion ofthe reaction, the reaction mixture was diluted with DCM and washed withwater, saturated NaHCO₃ solution, and 10% NaOH solution. The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum to afford pure tert-butyl4-(methoxy(methyl)carbamoyl)-piperidine-1-carboxylate product.

To a solution of tert-butyl4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (50 g, 182 mmol) inDCM (400 mL) was added trifluoroacetic acid (150 mL) and the resultingmixture was stirred for 6 h at 25-30° C. After completion of thereaction, the solvent was removed under reduced pressure to afford 40 gof N-methoxy-N-methylpiperidine-4-carboxamide product. [M+1]=173.04

STEP 2. 1-BENZYL-N-METHOXY-N-METHYLPIPERIDINE-4-CARBOXAMIDE

To the solution of N-methoxy-N-methylpiperidine-4-carboxamide (40 g, 232mmol) in acetone (400 mL) was added benzyl bromide (42 mL, 349 mmol) andK₂CO₃ (64 g, 465 mmol) and the reaction mixture was stirred at 80° C.under reflux for 16 h. After completion of the reaction, the reactionmixture was filtered and acetone was removed under reduced pressure. Theresidue was purified by silica gel column chromatography (eluting with50% ethyl acetate in hexane) to afford1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide product.[M+1]=263.15

STEP 3. 1-(1-BENZYLPIPERIDIN-4-YL)ETHANONE

To a stirred solution of1-benzyl-N-methoxy-N-methylpiperidine-4-carboxamide (11.5 g, 44 mmol) indiethyl ether (150 mL) at 0° C. was added methyl magnesium bromide (15.7g, 132 mmol), drop-wise over 10 min. The resulting mixture was stirredat 25-30° C. for 2 h. After completion of the reaction, the mixture wastreated with EtOAc and saturated NH₄Cl solution. The separated organiclayer was washed with brine and dried over anhydrous sodium sulfate andconcentrated under vacuum to afford 1-(1-benzylpiperidin-4-yl)ethanoneproduct. [M+1]=218.1

STEP 4. 2-(1-BENZYLPIPERIDIN-4-YL)-1,1,1-TRIFLUOROPROPAN-2-OL

To a stirred solution of potassium acetate (0.19 g, 1 mmol) indimethylformamide (2 mL) was added a solution of1-(1-benzylpiperidin-4-yl)ethanone (0.5 g, 2.3 mmol) indimethylformamide (2 mL) and CF₃SiMe₃ (0.67 mL, 4.6 mmol). The reactionmixture was stirred for 1 h at RT. After completion of the reaction, thereaction mixture was quenched with saturated aqueous NH₄Cl solution. Themixture was extracted with ethyl acetate and dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was purified bysilica gel column chromatography to afford1-benzyl-4-(1,1,1-trifluoro-2-(trimethylsilyloxy)propan-2-yl)piperidineproduct.

To a stirred solution of1-benzyl-4-(1,1,1-trifluoro-2-(trimethylsilyloxy)propan-2-yl)piperidine(3 g, 8.3 mmol) in THF (30 mL), tetrabutylammonium fluoride (3.2 g, 12.4mmol) was added slowly at RT. The reaction mixture was stirred for 3 h.After completion of the reaction, the mixture was quenched withsaturated ammonium chloride solution, extracted with ethyl acetate. Theorganic layer was washed with brine solution and dried over anhydroussodium sulfate and concentrated under vacuum to afford2-(1-benzylpiperidin-4-yl)-1,1,1-trifluoropropan-2-ol product.[M+1]=288.15

STEP 5. 1,1,1-TRIFLUORO-2-(PIPERIDIN-4-YL)PROPAN-2-OL

To a stirred solution of2-(1-benzylpiperidin-4-yl)-1,1,1-trifluoropropan-2-ol in methanol (25mL), palladium on carbon (150 mg, 3.26 mmol) was added under hydrogenatmosphere. The resulting mixture was stirred under reflux for 6 h at 65C. After completion of the reaction, the mixture was filtered andconcentrated under vacuum to afford1,1,1-trifluoro-2-(piperidin-4-yl)propan-2-ol. [M+H]=198.06

STEP 6.(S)-(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(4-(1,1,1-TRIFLUORO-2-HYDROXYPROPAN-2-YL)PIPERIDIN-1-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

Same as step 3 of example 1 to provide product. MS (ESI, pos. ion) m/z:512 (M+1). IC50 (uM) ++++.

Example 3(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-CHLOROPYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1: ETHYL 4-(4-METHOXYBENZYLOXY)BENZOATE

To a stirred solution of ethyl 4-hydroxybenzoate (530 g, 3.19 mol) inDMF (6 L) were added K₂CO₃ powder (1102 g, 7.97 mol, 2.5 eq.), NaI (1195g, 7.97 mol, 2.5 eq.) and PMB-Cl (599.4 g, 3.83 mol, 1.2 eq.) at ambienttemperature. The reaction mixture was heated at 50° C. overnight undernitrogen atmosphere. The reaction mixture was cooled to ambienttemperature and ice-water (9 L) was added to the reaction mixture. Theresulting solid was filtered and washed with water (5 L), dried at 40°C. under vacuum to obtain product.

STEP 2:(1H-BENZO[D]IMIDAZOL-2-YL)(4-(4-METHOXYBENZYLOXY)PHENYL)METHANONE

A solution of benzimidazole (450 g, 3.81 mol), triethyl orthoformate(1129.3 g, 7.62 mol, 2.0 eq.) and benzenesulphonic acid (16 g) intoluene (4 L) was heated to reflux, and half of the solvent was removedby distillation. Toluene (3 L) was added again and 2 L was removed byslow distillation. The reaction mixture was cooled, was neutralized withdiisopropylamine (55 mL), and to it were added THF (4 L) and 2 (1200 g,4.2 mol, 1.1 eq.). The mixture was cooled to −78° C. and to it was addedLDA (2.32 L, 2M in THF/hexane/ethylbenzene, 4.5 mol, 1.2 eq.) drop wiseover 3 h. After the addition, the reaction mixture was stirred at −78°C. for 2 h. It was then warmed to ambient temperature, 2N aqueous HCl(3.9 L) was added and the mixture was stirred for 2 h. The layers wereseparated, organic layer was washed with 10% aqueous NaHCO₃ solution andbrine, dried over Na₂SO₄, filtered and concentrated to give 2177 g crudeas an oil. To this crude were added MTBE (3 L) and hexanes (250 ml) andleft overnight in cold room. The resulting solid was filtered and washedwith MTBE, followed by 10% EtOAC/Hexanes to give product.

STEP 3: (1H-BENZO[D]IMIDAZOL-2-YL)(4-HYDROXYPHENYL)METHANONE

To a slurry of compound(1H-benzo[d]imidazol-2-yl)(4-(4-methoxybenzyloxy)phenyl)methanone (268g, 0.75 mol) in dichloromethane (2.7 L) at ambient temperature was addedTFA (289 mL, 3.75 mol, 5.0 eq.) slowly using an addition funnel. Thereaction was stirred at ambient temp for 16 h. LCMS analysis of thereaction mixture revealed that the reaction was complete. The reactionmixture was neutralized with satd. aqueous NaHCO₃ to pH=7-8, and stirredfor 20 minutes. The resulting solid was filtered and washed with waterand dried under vacuum oven at 45° C. to give product.

STEP 4:(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-CHLOROPYRAZIN-2-YLOXY)PHENYL)METHANONE

To a solution of compound(1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (100 g, 0.42 mol)in anhydrous DMF (1.1 L) was added K₂CO₃ (145 g, 1.05 mol, 2.5 eq.) and2,3-dichloropyrazine (75.08 g, 0.50 mol, 1.2 eq.). The reaction wasstirred at 90° C. for 18 h. LCMS analysis of the reaction mixture showedthat the reaction was complete. The reaction mixture was cooled toambient temperature and ice-water (3 L) was added, stirred for 30minutes. The resulting solid was filtered and washed with water (3 L)followed by MTBE (2×500 mL) and dried under vacuum. The solid wastreated with 50% MTBE/DCM at 50° C. for 1 h and filtered hot, washedwith 50% MTBE/DCM and dried under vacuum overnight to obtain product.Mother liquor was refluxed with 50% MTBE/DCM for 2 h and filtered hotand washed with 50% MTBE/DCM to get another batch of product. MS (ESI,pos. ion) m/z: 351.0 (M+1). IC50 (uM) +.

Example 4[4-(3-CHLORO-PYRAZIN-2-YLOXY)-PHENYL]-(6-FLUORO-1H-BENZOIMIDAZOL-2-YL)-METHANONE

STEP 1. 6-FLUORO-1H-BENZOIMIDAZOLE

To the solution of 4-fluoro-benzene-1,2-diamine (10 g, 79.4 mmol) andtriethylorthoformate (117 mL, 793 mmol) was added few drop of ethanoland the reaction mixture was refluxed at 150° C. overnight. The reactionmixture was concentrated and the residue was directly taken to the nextstep. [M+H]=137.

STEP 2. 6-FLUORO-BENZOIMIDAZOLE-1-CARBOXYLIC ACID TERT-BUTYL ESTER

To the solution of 6-fluoro-1H-benzoimidazole (21.5 g, 159 mmol) andtriethylamine (34.2 mL, 237 mmol) in DCM (200 mL) was addeddi-tert-butyl dicarbonate (41.3 mL, 190 mmol) at 5° C. The reactionmixture was stirred at RT overnight. The reaction was then diluted withDCM (100 mL) and washed with water (3×50 ml). The organic layer wasdried (Na₂SO₄) and concentrated. The crude product was purified bysilica gel (100-200 mesh) column using 5-10% ethyl acetate-hexane aseluent to obtain the title compound. [M+H]=237.

STEP 3.[4-(3-CHLORO-PYRAZIN-2-YLOXY)-PHENYL]-(6-FLUORO-1H-BENZOIMIDAZOL-2-YL)-METHANONE

A solution of 4-(3-Chloro-pyrazin-2-yloxy)-benzoic acid ethyl ester (20g, 84.7 mmol) and 6-fluoro benzoimidazole-1-carboxylic acid tert-butylester (21.2 g, 76.3 mmol) in freshly dried THF (150 mL) was cooled to−78° C. LiHMDS (106 mL, 106 mmol) was added slowly to it over 1.2 h. Thereaction mixture was stirred at the same temperature for 3.5 h. Thereaction was brought to −20° C. and slowly quenched with addition of 2NHCl until pH 3-4. The resulting mixture was stirred at RT for 1 h,extracted with ethyl acetate (3×200 mL), and washed with water (2×100mL). The organic layer was dried (Na₂SO₄) and concentrated. To the crudeproduct was added methanol (70 mL). After stirring for 1 h, the solidwas collected by filtration to give the title compound. MS (ESI, pos.ion) m/z: 369.2 (M+1). IC50 (uM) +.

Example 5(1-METHYL-1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-MORPHOLINOPYRAZIN-2-YLOXY)PHENYL)METHANONE

To a suspension of(1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)-phenyl)methanoneas prepared according to Scheme 3, (0.2 g, 0.5 mmol) in DMF (1 mL) wasadded cesium carbonate (0.2 g, 0.7 mmol) and iodomethane (0.04 mL, 0.6mmol). The resulting mixture was stirred at RT overnight. LC/MS showedcomplete conversion. Compound crashed out in MeOH. Filtered theresulting orange solid and rinse with copious amounts of MeOH. Solidswere dried by vacuum pump overnight to afford(1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone.MS (ESI, pos. ion) m/z: 416.1.(M+1). IC50 (uM) ++++.

Example 6(1-ISOPROPYL-1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-MORPHOLINOPYRAZIN-2-YLOXY)PHENYL)METHANONE

A mixture of(1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)-phenyl)methanone(115 mg, 286 μmol), potassium carbonate (79.2 mg, 573 μmol) and2-iodopropane (97.4 mg, 573 μmol) in DMF (2 mL) was stirred overnight.Additional isopropyl iodide was added until the starting material wasconsumed. The mixture was diluted with water and ethyl acetate. Thelayers were separated and the aqueous layer was extracted with ethylacetate and the combined organics were washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by Biotage™,10-30% acetone/hexanes gradient, to give(1-isopropyl-1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion)m/z: 444.1 (M+1). IC50 (uM) ++++.

Example 74-(3-(4-((1H-BENZO[D]IMIDAZOL-2-YL)DIFLUOROMETHYL)PHENOXY)PYRAZIN-2-YL)MORPHOLINE

A solution of(1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone(155 mg, 0.387 mmol) in Chloroform (15.500 ml) was cooled to 0° C. andDAST (1.023 ml, 7.74 mmol) was added. The ice bath was removed and thereaction was allowed to warm to room temperature. The reaction wasquenched with water and the mixture was diluted with dichloromethane.After separation of the layers, the aqueous layer was extracted withDCM. The combined organic layers were washed with brine, dried overNa2SO4, filtered and concentrated. The residue was purified by silicagel chromatography to give4-(3-(4-((1H-benzo[d]imidazol-2-yl)difluoromethyl)phenoxy)pyrazin-2-yl)morpholine.MS (ESI, pos. ion) m/z: 423.0 (M+1). IC50 (uM) +++.

TABLE (IA) EXAMPLES 8 TO 56 ARE TABULATED BELOW: Ex # Structure IUPACnames MS  8

(1H-benzo[d]imidazol-2- yl)(4-(3-(4-(2- hydroxypropan-2-yl)piperidin-1-yl)pyrazin- 2-yloxy)phenyl)methanone 458  9

(1H-benzo[d]imidazol-2- yl)(4-(3-(4- hydroxypiperidin-1- yl)pyrazin-2-yloxy)phenyl)methanone 416 10

(1H-benzo[d]imidazol-2- yl)(4-(3-(3- hydroxypiperidin-1- yl)pyrazin-1-yloxy)phenyl)methanone 416 11

(1H-benzo[d]imidazol-2- yl)(4-(3-(4- methoxypiperidin-1- yl)pyrazin-2-yloxy)phenyl)methanone 430 12

(1H-benzo[d]imidazol-2- yl)(4-(3-(pyrrolidin-1- yl)pyrazin-2-yloxy)phenyl)methanone 386 13

(1H-benzo[d]imidazol-2- yl)(4-(3-(piperidin-1- yl)pyrazin-2-yloxy)phenyl)methanone 400 14

(R)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(2- (methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy) phenyl)methanone 430 15

(1H-benzo[d]imidazol-2- yl)(4-(3-(2,6- dimethylmorpholino) pyrazin-2-yloxy)phenyl)methanone 430 16

(1H-benzo[d]imidazol-2- yl)(4-(3-(4- methylpiperazin-1- yl)pyrazin-2-yloxy)phenyl)methanone 415 17

1-(4-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)piperazin-1- yl)ethanone 443 18

1-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)piperidine-4- carbonitrile 425 19

(1H-benzo[d]imidazol-2- yl)(4-(3-(tetrahydro-2H-pyran-4-ylamino)pyrazin- 2-yloxy)phenyl)methanone 416 20

(1H-benzo[d]imidazol-2- yl)(4-(3-(tetrahydro-2H-pyran-3-ylamino)pyrazin- 2-yloxy)phenyl)methanone 416 21

(4-(3-(1,4-oxazepan-4- yl)pyrazin-2- yloxy)phenyl)(1H-benzo[d]imidazol-2- yl)methanone 416 22

(1H-benzo[d]imidazol-2- yl)(4-(3-(4- (methoxymethyl)piperidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 444 23

1-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)piperidin-4-one 414 24

(1H-benzo[d]imidazol-2- yl)(4-(3-(4- (trifluoromethyl)piperidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 468 25

(1H-benzo[d]imidazol-2- yl)(4-(3-(4-(2- hydroxyethyl)piperazin-1-yl)pyrazin-2- yloxy)phenyl)methanone 445 26

ethyl 2-(4-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)piperazin-1-yl)acetate 487 27

(1H-benzo[d]imidazol-2- yl)(4-(3-(6,7-dihydro-1H- imidazo[4,5-c]pyridin-5(4H)-yl)pyrazin-2- yloxy)phenyl)methanone 438 28

(1H-benzo[d]imidazol-2- yl)(4-(3-(4- methoxypiperidin-1- yl)pyrazin-2-yloxy)phenyl)methanone 430 29

8-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)-2-methyl-2,8- diazaspiro[4.5]decan-1-one 483 30

(1H-benzo[d]imidazol-2- yl)(4-(3-(4- morpholinopiperidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 485 31

(±)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(3- hydroxypyrrolidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 402

32

4-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)-1-methylpiperazin-2- one 429 33

(S)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(2- (hydroxymethyl)pyrrolidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 416 34

(S)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(3- (hydroxymethyl)pyrrolidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 416 35

(1H-benzo[d]imidazol-2- yl)(4-(3-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3- a]pyrazin-7(8H)- yl)pyrazin-2-yloxy)phenyl)methanone 453 36

(R)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(3- (hydroxymethyl)pyrrolidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 416 37

(S)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(2- (methoxymethyl)pyrrolidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 430 38

(1H-benzo[d]imidazol-2- yl)(4-(3-(4-(2- hydroxyethyl)piperidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 444 39

(±)-1-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)piperidine-3- carbonitrile 425 40

(±)-1-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3- carbonitrile 411 41

ethyl 1-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)piperidine-4- carboxylate 472 42

(±)-methyl 1-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3- carboxylate 444 43

(±)-ethyl 1-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)piperidine-3- carboxylate 472 44

(±)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(3-(3-methyl- 1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)pyrazin- 2-yloxy)phenyl)methanone 468 45

(S)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(3- hydroxypyrrolidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 402 46

(±)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(4-(1- hydroxyethyl)piperidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 444 47

1-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)piperidine-4- carboxylic acid 444 48

(±)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(3-(2- hydroxyethyl)piperidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 444 49

(1H-benzo[d]imidazol-2- yl)(4-(3-(4- (hydroxymethyl)piperidin-1-yl)pyrazin-2- yloxy)phenyl)methanone 430 50

(±)-(1H-benzo[d]imidazol- 2-yl)(4-(3-(3-(2- hydroxypropan-2-yl)piperidin-1-yl)pyrazin- 2-yloxy)phenyl)methanone 458 51

(±)-4-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)-6-methylpiperazin-2- one 429 52

(1H-imdiazol[4,5-b]pyridin- 2-yl)(4-(3- morpholinopyrazin-2-yloxy)phenyl)methanone 403 53

(4-(3-chloropyrazin-2- yloxy)phenyl)(1H- imidazo[4,5-b]pyridin-2-yl)methanone 352 54

(4-(3-chloropyrazin-2- yloxy)phenyl)(7-fluoro- 1H-benzo[d]imidazol-2-yl)methanone 369 55

(4-(3-chloropyrazin-2- yloxy)phenyl)(1-methyl- 1H-benzo[d]imidazol-2-yl)methanone 365 56

(1H-benzo[d]imidazol-2- yl)(4-(3-(3- hydroxyazetidin-1- yl)pyrazin-2-yloxy)phenyl)methanone 388

TABLE (1B) PREPARATION OF EXAMPLES 8 TO 56 ARE TABULATED BELOW:Synthetic How different Ex # Scheme from main route Reagent difference 8 1 Same

 9 1 Same

10 1 Same

11 1 1 eq TEA, 90° C., 1.5 h, not sealed

12 1 Same

13 1 Same

14 1 70° C., 5 h, not sealed

15 1 90° C., 9 h, not sealed

16 1 Same

17 1 Same

18 1 Same

19 1 iPr₂NEt, 200° C., microwave

20 1 K₂CO₃, 200° C., microwave

21 1 70° C., 5 h, not sealed

22 1 70° C., 5 h, not sealed

23 1 (1) Cs₂CO₃, 90° C. (2) TFA  

24 1 Same

25 1 Same

26 1 Same

27 1 Same

28 1 1.0 equivalents of triethylamine was added to the reaction

29 1 3.0 equivalents of cesium carbonate was added to the reaction

30 1 3.0 equivalents of cesium carbonate was added to the reaction

31 1 Same

32 1 1.0 equivalents of triethylamine was added to the reaction

33 1 1.0 equivalents of triethylamine was added to the reaction

34 1 4.5 equivalents of triethylamine was added to the reaction

35 1 1.0 equivalents of triethylamine was added to the reaction

36 1 1.0 equivalents of triethylamine was added to the reaction

37 1 1.0 equivalents of triethylamine was added to the reaction

38 1 1.0 equivalents of triethylamine was added to the reaction

39 1 Same

40 1 1.0 equivalents of triethylamine was added to the reaction

41 1 3.0 equivalents of triethylamine was added to the reaction

42 1 3.0 equivalents of triethylamine was added to the reaction

43 1 Same

44 1 Same

45 1 Same

46 1 Same

47 1 Workup: HCl

48 1 Same

49 1 Same

50 1 6.0 equivalents of triethylamine was added to the reaction

51 1 Same

52 1 Same

53 1 Same

54 1 Same

55 4 Same

56 1 C₂CO₃, NMP, 135° C.

Example 57(S)-N-(4-(3-(2-(METHOXYMETHYL)PYRROLIDIN-1-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

STEP 1. 4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOL

The solution of 2-chlorobenzothiazole (2.47 mL, 20 mmol) and4-aminophenol (2.18 g, 20.0 mmol) in N-methylpyrrolidone (16 mL) washeated at 160° C. for 7 h. The reaction mixture was quenched withaqueous 2N NaOH and then extracted with EtOAc. The organic layer waswashed with 2N NaOH. To the combined aqueous layer was added aqueous 5NHCl until pH 6, then the product was extracted with EtOAc (2×), dried(Na₂SO₄) and concentrated. The crude product was dissolved in MeOH andtreated with SiO₂. Chromatograph through a Redi-Sep® pre-packed silicagel column (120 g), eluting with a gradient of 0% to 50% EtOAc inhexane, provided 4-(benzo[d]thiazol-2-ylamino)phenol as a tan solid.

STEP 2. N-(4-(3-CHLOROPYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (3.1 g, 12.8 mmol)and 2,3-dichloropyrazine (2.29 g, 15.4 mmol) in DMSO (35 mL) was addedcesium carbonate (5.0 g, 15.4 mmol). The reaction mixture was heated to80° C. for 2 h. The mixture was cooled to RT, diluted with EtOAc andbrine. The aqueous layer was extracted with EtOAc (2×) and the combinedorganics were dried over Na₂SO₄, filtered and concentrated. The crudeproduct was chromatographed through a Redi-Sep® pre-packed silica gelcolumn (120 g), eluting with a gradient of 0% to 100% EtOAc in hexane,to provide N-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amineas light-tan solid.

STEP 3.(S)-N-(4-(3-(2-(METHOXYMETHYL)PYRROLIDIN-1-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

To a solution ofN-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (180 mg,0.51 mmol) in DMSO (2 mL) was added(s)-(+)-2-(methoxymethyl)-pyrrolidine (0.29 mL, 2.55 mmol). The reactionmixture was heated at 80° C. for 16 h. The reaction mixture waspartitioned between EtOAc and brine. The aqueous layer was backextracted with EtOAc (2×) and the combined organics were dried (Na₂SO₄)and concentrated. The crude product was chromatographed through aRedi-Sep® pre-packed silica gel column (40 g), eluting with a gradientof 0% to 40% EtOAc in hexanes, followed by reverse-phase preparativeHPLC using a Phenomenex Gemini™ column (10 micron, C18, 110 Å, 150×30mm), 0.1% TFA in CH₃CN/H₂O as mobile phase, gradient 10% to 90% over 15min., then treated with Si-carbonate resin to provide(S)-N-(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amineas off-white solid. MS (ESI, pos. ion) m/z: 434.1 (M+1). IC50 (uM)+++++.

Example 58N-(4-(3-(TETRAHYDRO-2H-PYRAN-3-YLAMINO)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

To a microwave vial was charged withN-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.25 g,0.71 mmol), tetrahydro-2H-pyran-3-amine hydrochloride (0.19 g, 1.4mmol), and DIPEA (0.49 mL, 2.8 mmol) in isopropyl alcohol (2 mL). Thereaction was stirred and heated in a Discover® model microwave reactor(CEM, Matthews, N.C.) at 200° C. for 30 min (200 watts, Powermax™feature on), then at the same temperature for another 15 min. Thereaction mixture was partitioned between EtOAc and brine. The aqueouslayer was extracted with EtOAc (3×) and the combined organics was dried(Na₂SO₄) and concentrated. The crude product was chromatographed througha Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradientof 0% to 50% EtOAc in hexane, to provideN-(4-(3-(tetrahydro-2H-pyran-3-ylamino)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amineas off-white solid. MS (ESI, pos. ion) m/z: 420.0 (M+1). IC50 (uM) ++++.

Example 59(S)-2-(1-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)PYRROLIDIN-2-YL)PROPAN-2-OL

STEP 1. (S)-METHYL 1-BENZYLPYRROLIDINE-2-CARBOXYLATE

1-proline methyl ester hydrochloride (5.8 g, 35 mmol) was suspended inDCM (40 mL), to it was added triethylamine (12 ml, 84 mmol). Afterstirring for 10 min, the precipitate formed was filtered off and washedwith DCM (5 mL). To the filtrate was added benzyl bromide (5.0 ml, 42mmol). The reaction mixture was stirred at RT for 16 h. The reactionmixture was diluted with EtOAc and washed with water and brine, dried(Na2SO4) and concentrated. The crude product was chromatographed througha Redi-Sep® pre-packed silica gel column (120 g), eluting with agradient of 0% to 25% EtOAc in hexane, to provide (S)-methyl1-benzylpyrrolidine-2-carboxylate as colorless oil. MS (ESI, pos. ion)m/z: 220.0 (M+1).

STEP 2. (S)-2-(PYRROLIDIN-2-YL)PROPAN-2-OL

Methylmagnesium chloride, 3.0 m solution in tetrahydrofuran (24 ml, 71mmol) was slowly injected into a solution of (S)-methyl1-benzylpyrrolidine-2-carboxylate (3.87 g, 18 mmol) in dry THF (50 mL)at 0° C. The reaction mixture was stirred at that temperature for 3.5 h.The reaction was quenched with saturated NH₄Cl and extracted with EtOAc(3×). The combined organic layers were washed with water and brine,dried (Na₂SO₄) and concentrated. The residue was chromatographed througha Redi-Sep® pre-packed silica gel column (120 g), eluting with agradient of 0% to 50% EtOAc in hexane, to provide(S)-2-(1-benzylpyrrolidin-2-yl)propan-2-ol as clear oil.

To a solution of (S)-2-(1-benzylpyrrolidin-2-yl)propan-2-ol (1.38 g,6.29 mmol) in MeOH (50 mL) was added palladium hydroxide, 20 wt % pd(dry basis) on carbon, wet, degussa type e101 ne/w (230 mg, 1.64 mmol)and acetic acid glacial (690 μl, 12.0 mmol). The reaction mixture wasstirred at RT under 1 atm of H₂ for 24 h. The reaction mixture wasfiltered through a pad of celite and washed with MeOH. The solvent wasevaporated and the residue was partitioned between 2 N NaOH and EtOAc.The aqueous layer was extracted with EtOAc (2×) and the combined organiclayer was dried (Na₂SO₄) and concentrated. The crude product waschromatographed through a Redi-Sep® pre-packed silica gel column (40 g),eluting with a gradient of 50% to 100% MeOH in EtOAc, to provide(S)-2-(pyrrolidin-2-yl)propan-2-ol as an orange oil.

STEP 3.(S)-2-(1-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)PYRROLIDIN-2-YL)PROPAN-2-OL

To a solution ofN-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (180 mg,507 μmol) in DMSO (2 mL) was added (S)-2-(pyrrolidin-2-yl)propan-2-ol(216 mg, 1674 μmol). The reaction mixture was heated at 80° C. for 16 h,then at 100° C. for 72 h.

The reaction mixture was partitioned between EtOAc and brine. Theaqueous layer was back extracted with EtOAc (2×) and the combinedorganics were dried (Na₂SO₄) and concentrated. The crude product waschromatographed through a Redi-Sep® pre-packed silica gel column (40 g),eluting with a gradient of 0% to 40% EtOAc in hexane to provide(S)-2-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-2-yl)propan-2-olas tan solid. MS (ESI, pos. ion) m/z: 448.1 (M+1). IC50 (uM) +++++.

Example 601-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)-4-METHYLPIPERIDIN-4-OL

STEP 1. 4-METHYLPIPERIDIN-4-OL HYDROCHLORIDE

To tert-butyl 4-hydroxy-4-methylpiperidine-1-carboxylate (1.0 g, 4.6mmol) was added hydrogen chloride, 1.0 M solution in diethyl ether (4.6ml, 4.6 mmol). The reaction mixture was stirred at RT for 4 h. Thereaction mixture was concentrated down to give a yellow oil which wasused directly in the following step.

STEP 2:1-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)-4-METHYLPIPERIDIN-4-OL

The crude material from previous step was trituated with ether/DCM. Thesolvent was decanted and the residue was concentrated to give alight-yellow solid. To it was addedN-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (180 mg,0.507 mmol), cesium carbonate (496 mg, 1.522 mmol) and DMSO (2.0 mL).The reaction mixture was stirred at 80° C. for 16 h. The reactionmixture was partitioned between EtOAc and brine. The aqueous layer wasback extracted with EtOAc (2×) and the combined EtOAc layer was dried(Na₂SO₄) and concentrated. The crude material was dissolved in DCM andpurified by chromatography through a Redi-Sep® pre-packed silica gelcolumn (40 g), eluting with a gradient of 0% to 70% EtOAc in hexane, toprovide1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-4-methylpiperidin-4-olas light-yellow solid. MS (ESI, pos. ion) m/z: 434.1 (M+1) . . . IC50(uM) +++++.

Example 61BENZO[D]THIAZOL-2-YL(4-(3-MORPHOLINOPYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1. 4-BENZYLOXY-BENZOIC ACID METHYL ESTER

In a 2 L two-necked round bottom flask was charged methyl4-hydroxybenzoate (100 g, 0.657 mol) and 500 mL of DMF. Potassiumcarbonate (180 g, 1.3 mol) was added and the mixture was cooled to 0° C.Benzylbromide (77 mL, 0.66 mol) was added dropwise to the reactionmixture with vigorous stirring for 30 min. After the addition wascomplete, the reaction mixture was stirred for 8 h at RT, then dilutedwith 500 ml water. The solid precipitated was collected by filtrationand washed with water. Drying in a vacuum oven overnight provided thetitle compound.

STEP 2. BENZO[D]THIAZOL-2-YL(4-(BENZYLOXY)PHENYL)METHANONE

In a 100 ml round bottom flask were added 4-benzyloxy-benzoic acidmethyl ester (0.8 g, 3.1 mmol) and benzothiozole (312 mg, 3.1 mmol),followed by dry THF. After cooling the reaction mixture to −70° C., LDA(15.2 mL 1.6 M, 18.6 mmol) was added slowly for 5 min. The reactionmixture was stirred −70° C. for 2 h. The reaction was quenched with 1NHCl and extracted with ethyl acetate. The aqueous was back extractedwith EtOAc and the combined organics was washed with brine and dried(Na₂SO₄) and concentrated to givebenzo[d]thiazol-2-yl(4-(benzyloxy)phenyl)methanone.

STEP 3. BENZO[D]THIAZOL-2-YL(4-HYDROXYPHENYL)METHANONE

In a 1 L round bottom flask was charged in a solution of borontrifluride diethyl etherate (101.2 g, 312 mmol) and dimethylsulfide (112g, 809 mmol) in dry methylenedichloride (300 ml).Benzo[d]thiazol-2-yl(4-(benzyloxy)phenyl)methanone (30 g, 86.9 mmol) wasadded slowly to the mixture and the resulting solution was stirred atroom temperature for 72 h. The reaction mixture was then quenched withwater and diluted with CH₂Cl₂. The organic phase was washed with brine,dried (Na2SO4) and concentrated. The crude product was purified bysilica gel column chromatography with hexane and ethyl acetate to givebenzo[d]thiazol-2-yl(4-hydroxyphenyl)methanone. [M+H]=256.

STEP 4: BENZO[D]THIAZOL-2-YL(4-(3-CHLOROPYRAZIN-2-YLOXY)PHENYL)METHANONE

In 250 mL round bottom flask were chargedbenzo[d]thiazol-2-yl(4-hydroxyphenyl)methanone (6.0 g, 23.5 mmol),2,3-dichloro-pyrazine (3.48 g, 23.5 mmol), DMSO (60 mL), and cesiumcarbonate (15 g, 47 mmol). The reaction mixture was stirred at 90° C.for 6 h. The reaction mixture was diluted with cold water and theprecipitate was collected by filtration. The crude product was purifiedby silica gel column chromatography with hexane and ethyl acetate togive the title compound. [M+H]=368.

STEP 5.BENZO[D]THIAZOL-2-YL(4-(3-MORPHOLINOPYRAZIN-2-YLOXY)PHENYL)METHANONE

To a solution ofbenzo[d]thiazol-2-yl(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (185mg, 0.503 mmol) in DMSO (2 mL) was added morpholine (219 μl, 2.52 mmol).The reaction mixture was heated at 100° C. for 2 h. The reaction mixturewas partitioned between EtOAc and brine. The precipitate formed wascollected by filtration, washed with EtOAc and water, dried to providebenzo[d]thiazol-2-yl(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone aslight-yellow solid. MS (ESI, pos. ion) m/z: 419.0. IC50 (uM) ++.

Example 62N-(4-(3-CHLOROPYRAZIN-2-YLOXY)PHENYL)-6-FLUOROBENZO[D]THIAZOL-2-AMINE

STEP-1. 6-FLUOROBENZO[D]THIAZOLE-2-THIOL

4-Fluorobenzene-1,2-diamine (10.0 g, 0.077 mol) and potassium O-ethylcarbonodithioate (37.1 g, 0.234 mol) were dissolved in dry DMF (150 mL)under nitrogen and heated to 95° C. for 12 h. The reaction was cooled toRT and 200 mL water was added followed by addition of 5N HCl to getprecipitates. After stirring for 1 h, the precipitates were collected byfiltration, washed with water and dried under vacuum for 2 h. The crudecompound was then washed with chloroform and dried to give6-fluorobenzo[d]thiazole-2-thiol as yellow solid.

STEP-2. 2-CHLORO-6-FLUOROBENZO[D]THIAZOLE

6-fluorobenzo[d]thiazole-2-thiol (14.0 g, 0.075 mol) was suspended indry DCM (100 mL) under nitrogen and cooled to 0° C. Sulfuryl chloride(18.5 mL) was then added dropwise and the reaction was allowed to warmto RT and stirred for 1 h. The reaction mixture was then poured on tocrushed ice and extracted with DCM (4×300 mL). The combined organicextract was given brine wash (2×150 mL), dried (Na₂SO₄) andconcentrated. The crude compound was purified by column chromatography(Silica 100-200 mesh; 3-7% ethyl acetate in hexane) to provide2-chloro-6-fluorobenzo[d]thiazole as a white solid.

STEP-3. 4-(6-FLUOROBENZO[D]THIAZOL-2-YLAMINO)PHENOL

2-Chloro-6-fluorobenzo[d]thiazole (7.0 g, 0.037 mol) and 4-aminophenol(4.0 g, 0.037 mol) in NMP (50 mL) was heated at 160° C. for 7 h. Thereaction was quenched with 2N NaOH (100 mL) and then extracted withEtOAc (2×100 mL). The organic layer was washed with 2 N NaOH (50 mL) andto the combined aqueous layer was added 5 N HCl until pH 6 and thenextracted with EtOAc (3×200 mL). The combined organic extracts werewashed with brine, dried (Na₂SO₄) and concentrated. The crude waspurified by column chromatography (silica gel 100-200 mesh; 80% ethylacetate in hexanes) to afford4-(6-fluorobenzo[d]thiazol-2-ylamino)phenol as a white solid.

STEP-4.N-(4-(3-CHLOROPYRAZIN-2-YLOXY)PHENYL)-6-FLUOROBENZO[D]THIAZOL-2-AMINE

To a solution of 4-(6-fluorobenzo[d]thiazol-2-ylamino)phenol (7.5 g,0.028 mol) and 2,3-dichloropyrazine (5.0 g, 0.034 mol) in DMSO (35 mL)was added cesium carbonate (11.0 g, 0.034 mol). The mixture was heatedto 80° C. for 2 h. The reaction mixture was cooled to RT and dilutedwith water (350 mL). The aqueous layer was extracted with EtOAc (4×300mL). The combined organic extract was washed with brine, dried (Na₂SO₄)and concentrated. The crude product was purified by columnchromatography (silica 100-200 mesh; 30-60% ethyl acetate in hexane) togiveN-(4-(3-chloropyrazin-2-yloxy)phenyl)-6-fluorobenzo[d]thiazol-2-amine asa white solid. [M+H]=372.8. IC50 (uM) +.

Example 63N-(4-(3-MORPHOLINOPYRAZIN-2-YLOXY)PHENYL)-1H-BENZO[D]IMIDAZOL-2-AMINE

STEP 1. 4-(3-CHLOROPYRAZIN-2-YLOXY)BENZENAMINE

2,3-dichloropyrazine (470 mg, 3155 μmol) was combined with 4-aminophenol(344 mg, 3155 μmol) and cesium carbonate (1233 mg, 3786 μmol) in DMSO (5ml) and heated to 70 C. After 3 hours, the mixture was cooled to roomtemperature, transferred to a separatory funnel rinsing with ethylacetate and water, the layers were separated and the aqueous wasextracted with ethyl acetate (3×). The combined organics were rinsedwith brine, dried over sodium sulfate, filtered and concentrated toyield a brown solid which was carried forward without purification.

STEP 2. CHLORO-3-(4-ISOTHIOCYANATOPHENOXY)PYRAZINE

To a mixture of 4-(3-chloropyrazin-2-yloxy)benzenamine (620 mg, 2797μmol) and sodium carbonate (652 mg, 6154 μmol) in chloroform (10 ml) wasadded thiophosgene (236 μl, 3077 μmol). The solution turned cloudy andwas stirred overnight at room temperature. The solvent had evaporated sothe residue was taken back up in chloroform and the solids were removedby filtration. The filtrate was collected and the solvent was removed byroto-vap to give the desired product as a brown solid which was usedwithout further purification.

STEP 3.N-(4-(3-CHLOROPYRAZIN-2-YLOXY)PHENYL)-1H-BENZO[D]IMIDAZOL-2-AMINE

The mixture of 2-chloro-3-(4-isothiocyanatophenoxy)pyrazine (190 mg, 721mmol), benzene-1,2-diamine (93.5 mg, 865 μmol) andN,N′-dicyclohexylcarbodiimide (223 mg, 1081 μmol) in THF (1.5 ml) washeated at 75° C. for 1.5 hrs. The mixture was cooled to roomtemperature, diluted with DCM and absorbed onto silica for purificationusing a 20-100% EtOAc/hexanes gradient to give the desired product.

STEP 4.N-(4-(3-MORPHOLINOPYRAZIN-2-YLOXY)PHENYL)-1H-BENZO[D]IMIDAZOL-2-AMINE

N-(4-(3-chloropyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine (191mg, 565 μmol) and morpholine (74 μL, 848 μmol) in DMSO was heated to 80°C. After 3 h, starting material remained so additional morpholine (74uL, 848 umol) was added and the mixture was heated overnight. The hotsolution was then poured onto ice water which caused a brown solid toprecipitate. The solid was collected by filtration, washed and dried togive the desired product. MS (ESI, pos. ion) m/z: 389.1 (M+1). IC50 (uM)+++++.

TABLE (IIA) EXAMPLES 64 TO 103 ARE TABULATED BELOW: IC50 Ex # Structure(uM) IUPAC names MS 64

++++ 5-fluoro-N-(4-(3- morpholinopyrazin- 2-yloxy)phenyl)-1H-benzo[d]imidazoL-2- amine 407 65

+++++ N-(4-(3- morpholinopyrazin- 2- yloxy)phenyl) benzo[d]thiazol-2-amine 406 66

+++++ 2-(1-(3-(4- benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperidin-4-yl) propan-2-ol 462 67

+++++ 1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperidin-4-ol 420 68

++++ N-(4-(3-(pyrrolidin- 1-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2-amine 390 69

+++++ 1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperidin-3-ol 420 70

+++++ 1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperidine-4- carbonitrile 429 71

++++ 1-(4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperazin-1-yl) ethanone 447 72

++++ N-(4-(3-(4- methylpiperazin-1- yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2-amine 419 73

++ 2-(1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperidin-4-yl)-1,1,1- trifluoropropan-2-ol 516 74

++++ N-(4-(3-(2,6- dimethylmorpholino) pyrazin-2-yloxy) phenyl)benzo[d]thiazol-2-amine 434 75

++ N-(4-((3-(1,1- dioxido-4- thiomorpholinyl)-2- pyrazinyl)oxy)phenyl)-1,3- benzothiazol-2- amine 454 76

+++++ (S)-(1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)pyrrolidin-2-yl) methanol 420 77

++++ N-(4-(3-(azetidin-1- yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2-amine 376 78

+++++ 1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)azetidine-3- carboxylic acid 420 79

+++++ 2-(4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperazin-1-yl) ethanol 449 80

++++ N-(4-(3-(6,7- dihydro-1H- imidazo[4,5- c]pyridin-5(4H)-yl)pyrazin-2- yloxy)phenyl)benzo [d]thiazol-2-amine 442 81

+++++ 1-(3-(4- benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperidine-4- carboxamide 447 82

+++ N-(4-(3-(2-methyl- 6,7-dihydro-1H- imidazo[4,5- c]pyridin-5(4H)-yl)pyrazin-2- yloxy)phenyl)benzo [d]thiazol-2-amine 456 83

+++++ methyl 1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)azetidine-3- carboxylate 434 84

+++++ 1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)pyrrolidine-3- carbonitrile 415 85

+++++ (R)-(1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)pyrrolidin-3- yl)methanol 420 86

++++ 2-(1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperidin-4-yl) ethanol 448 87

++++ N-(4-(3-(4- (methoxymethyl) piperidin-1-yl) pyrazin-2-yloxy)phenyl)benzo[d] thiazol-2-amine 448 88

+++++ N-(4-(3-(3- (methoxymethyl) pyrrolidin-1-yl) pyrazin-2-yloxy)phenyl)benzo[d] thiazol-2-amine 434 89

+++++ (1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperidin-4-yl) methanol 434 90

+++++ 4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperazin-2-one 434 91

++++ 4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)-1-isopropylpiperazin- 2-one 461 92

+++++ N-(4-(3-(4- methoxypiperidin-1- yl)pyrazin-2-yloxy)phenyl)benzo[d] thiazol-2-amine 434 93

++++ 1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)azetidine-3- carbonitrile 401 94

+++++ 4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)-6-methylpiperazin-2- one 433 95

++++ 1-(1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperidin-4-yl) ethanol 448 96

+++++ methyl 1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)pyrrolidine-3- carboxylate 448 97

+++++ (1-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)piperidin-2-yl) methanol 434 98

++++ N-(4-(3-(3- (methoxymethyl) piperidin-1-yl) pyrazin-2-yloxy)phenyl)benzo[d] thiazol-2-amine 448 99

++++ N-(4-(3-(1,4-dioxa- 8- azaspiro[4.5]decan- 8-yl)pyrazin-2-yloxy)phenyl)benzo [d]thiazol-2-amine 462 100 

+ N-(4-(3- chloropyrazin-2- yloxy)phenyl)-7- fluorobenzo[d]thiazol-2-amine 372 101 

+ N-(4-(3- chloropyrazin-2- yloxy)phenyl)-6- fluorobenzo[d]thiazol-2-amine 372 102 

+ N-(4-(3- chloropyrazin-2- yloxy)phenyl)-5- fluorobenzo[d]thiazol-2-amine 372 103 

+ N-(4-(3- chloropyrazin-2- yloxy)-2- fluorophenyl)benzo[d]thiazol-2-amine 372

TABLE (IIB) PREPARATION OF EXAMPLES 64 TO 103 ARE TABULATED BELOW:Synthetic How Different from Reagent Ex # Scheme Main Route Difference64 7 Same

65 5 Same

66 5 Same

67 5 Same

68 5 Same

69 5 Same

70 5 Same

71 5 Same

72 5 Same

73 5 Same

74 5 Same

75 5 Same

76 5 Same

77 5 Same

78 5 Same

79 5 Same

80 5 Same

81 5 Same

82 5 Same

83 5 Cs₂CO₃

84 5 Cs₂CO₃

85 5 Cs₂CO₃

86 5 Same

87 5 Cs₂CO₃

88 5 Cs₂CO₃

89 5 Same

90 5 Same

91 5 Cs₂CO₃

92 5 Same

93 5 Cs₂CO₃

94 5 Same

95 5 Same

96 5 Cs₂CO₃

97 5 Same

98 5 Same

99 5 Same

100  6 Same

101  6 Same

102  6 Same

103  6 Same

Example 104(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(2-(TRIFLUOROMETHYL)PYRIDIN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

A mixture of(1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone(300 mg, 0.855 mmol), potassium phosphate (545 mg, 2.57 mmol),2-(trifluoromethyl)pyridin-4-ylboronic acid (490 mg, 2.57 mmol), andBis-[4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine]palladiumdichloride (121 mg, 0.171 mmol) in dimethoxyethane was heated to 80° C.Following complete reaction, the mixture was cooled to room temperaturewhich caused a solid to precipitate which was collected by filtrationand dried to give(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(trifluoromethyl)pyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone.MS (ESI, pos. ion) m/z: 461.0 (M+1). IC50 (uM) +++++.

Example 105(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(2-(4-METHOXYBENZYLOXY)PYRIDIN-3-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1.(5-FLUORO-1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(2-METHOXYPYRIDIN-3-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

To a microwave safe 30 ml tubes were charged with(1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone(0.500 g, 1.43 mmol), 2-fluoropyridin-3-ylboronic acid (0.241 g, 1.71mmol), tetrakis(triphenylphosphine)palladium(0) (0.165 g, 0.143 mmol)and a 2M solution of sodium carbonate monohydrate (2.14 mL, 4.28 mmol)in 1,4-dioxane. The flasks were sealed and heated to 150° C. for 45 minin a microwave. The reaction mixture was diluted with DCM (75 mL),washed with water and brine. It was dried over magnesium sulfate,concentrated and dried in vacuo. It was suspended in DCM/MeOH andstirred. The insoluble material was collected by filtration,recrystallized overnight from boiling MeOH and hexane, then dried in avacuum oven to give(1H-benzo[d]imidazol-2-yl)(4-(3-(2-fluoropyridin-3-yl)pyrazin-2-yloxy)phenyl)methanoneas yellow solid. LC/MS: MS (ESI, pos. ion) m/z: 412.1 (M+1).

STEP. 2.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(2-(4-METHOXYBENZYLOXY)PYRIDIN-3-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

To a mixture of(1H-benzo[d]imidazol-2-yl)(4-(3-(2-fluoropyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone(200 mg, 0.486 mmol) and 4-methoxybenzyl alcohol (0.905 mL, 7.29 mmol)in toluene in a 6 mL tube was added potassium tert-butoxide, 1.0 msolution in 2-methyl-2-propanol (2.431 mL, 2.431 mmol). The reaction washeated to 80° C. After 7 min a mixture of products was observed byLC/MS. The mixture was diluted with DCM (30 mL), and washed with water(3×25 mL) and brine (30 mL). It was dried over magnesium sulfate,concentrated and dried in vacuo. It was purified by flash chromatography(40 g SiliaSep pre-packed silica gel column, eluent: 0-40% EtOAc inhexane) to give(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(4-methoxybenzyloxy)pyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone.MS (ESI, pos. ion) m/z: 532.0 (M+1).

Example 1063-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)PYRIDIN-2(1H)-ONE

To a suspension of(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(4-methoxybenzyloxy)pyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone(0.050 g, 0.094 mmol) in DCM/water in a 50 mL round bottom flask wasadded DDQ (0.026 g, 0.113 mmol) and dioxane (1 mL). The mixture wasstirred at 60° C. for 16 h. The mixture was diluted with saturatedNaHCO₃ and extracted with DCM (3×25 mL). The combined organic layer waswashed with saturated NaHCO₃ and brine. The insoluble material wascollected, washed with ethanol, filtered and dried in vacuo to give3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyridin-2(1H)-one.MS (ESI, pos. ion) m/z: 410.2 (M+1). IC50 (uM) +++++.

TABLE (IIIA) EXAMPLES 107 TO 134 ARE TABULATED BELOW: IC50 Ex #Structure (uM) IUPAC names MS 107

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(2- methylpyridin-4-yl)pyrazin-2- yloxy)phenyl)methanone 408 108

+++++ 4-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)benzonitrile 418 109

++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(2- methylpyridin-3- yl)pyrazin-2-yloxy)phenyl)methanone 408 110

++++ (1-methyl-1H- benzo[d]imidazol-2- yl)(4-(3-(2- methylpyridin-3-yl)pyrazin-2- yloxy)phenyl)methanone 422 111

++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(2,6- dimethoxypyridin-3-yl)pyrazin-2- yloxy)phenyl)methanone 454 112

++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(4- methoxypyridin-3-yl)pyrazin-2- yloxy)phenyl)methanone 424 113

++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(3- methoxypyridin-4-yl)pyrazin-2- yloxy)phenyl)methanone 424 114

++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(2- methoxyphenyl)pyrazin- 2-yloxy)phenyl)methanone 423 115

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(2- methoxyquinolin-3-yl)pyrazin-2- yloxy)phenyl)methanone 474 116

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(5-fluoro-2- methoxypyridin-3-yl)pyrazin-2- yloxy)phenyl)methanone 424 117

++++ (5-fluoro-1H- benzo[d]imidazol-2- yl)(4-(3-(2- methoxypyridin-3-yl)pyrazin-2- yloxy)phenyl)methanone 442 118

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(5- methoxypyridin-3-yl)pyrazin-2- yloxy)phenyl)methanone 424 119

+++++ (4-(3-(2- methoxypyridin-3- yl)pyrazin-2- yloxy)phenyl)(1-methyl-1H- benzo[d]imidazol-2- yl)methanone 438 120

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(2- methoxypyridin-4-yl)pyrazin-2- yloxy)phenyl)methanone 424 121

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(6- methoxypyridin-3-yl)pyrazin-2- yloxy)phenyl)methanone 424 122

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(2- methoxypyridin-3-yl)pyrazin-2- yloxy)phenyl)methanone 424 123

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(pyridin-3- yl)pyrazin-2-yloxy)phenyl)methanone 394 124

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(pyridin-4- yl)pyrazin-2-yloxy)phenyl)methanone 394 125

+++++ 3-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)benzonitrile 418 126

+++++ methyl 4-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)benzoate 451 127

+++++ 4-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)benzoic acid 437 128

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(3- methoxyphenyl)pyrazin- 2-yloxy)phenyl)methanone 423 129

++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(quinolin-4- yl)pyrazin-2-yloxy)phenyl)methanone 444 130

++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(quinolin-5- yl)pyrazin-2-yloxy)phenyl)methanone 444 131

++++ (4-(3-(3,6-dihydro-2H- pyran-4-yl)pyrazin-2- yloxy)phenyl)(1H-imidazo[4,5-b]pyridin- 2-yl)methanone 400 132

++++ 2-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)-4,4- dimethylcyclohex-2- enone 439 133

+++++ 1-(4-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)-5,6- dihydropyridin-1(2H)- yl)ethanone 440 134

+++++ (1-(2-fluoroethyl)-1H- benzo[d]imidazol-2- yl)(4-(3-(2-methoxypyridin-3- yl)pyrazin-2- yloxy)phenyl)methanone 470

TABLE (IIIB) PREPARATION OF EXAMPLES 107 TO 134 ARE TABULATED BELOW:Synthetic How different Ex # Scheme from main route Reagent difference107 8 Same

108 8 Same

109 8 Same

110 4 Same

111 8 PdCl₂(PPh₃)₂, Na₂CO₃ 140° C., microwave

112 8 PdCl₂(PPh₃)₂, K₂CO₃, 140° C., microwave

113 8 T: 130° C.

114 8 K₃PO₄, A-Phos, 150° C., microwave

115 8 K₃PO₄, A-Phos, 150° C., microwave

116 8 K₃PO₄, A-Phos, 150° C., microwave

117 8 K₃PO₄, A-Phos, 150° C., microwave

118 8 K₃PO₄, A-Phos, 150° C., microwave

119 8 K₃PO₄, A-Phos, 150° C., microwave

120 8 K₃PO₄, A-Phos, 150° C., microwave

121 8 K₃PO₄, A-Phos, 150° C., microwave

122 8 K₃PO₄, A-Phos, 150° C., microwave

123 8 PdCl₂(^(t)Bu₂PhP)₂, KOAc, 100° C.,

124 8 PdCl₂(^(t)Bu₂PhP)₂, KOAc, 100° C.,

125 8 PdCl₂(^(t)Bu₂PhP)₂, KOAc, 100° C.,

126 8 PdCl₂(^(t)Bu₂PhP)₂, KOAc, 100° C.,

127 8 LiOH, THF/H₂O

128 8 PdCl₂(^(t)Bu₂PhP)₂, KOAc, 100° C.,

129 8 PdCl₂(^(t)Bu₂PhP)₂, KOAc, 100° C.,

130 8 PdCl₂(^(t)Bu₂PhP)₂, KOAc, 100° C.,

131 8 PdCl₂(PPh₃P)₂, Na₂CO₃,

132 8 PdCl₂(^(t)Bu₃P)₂, K₂CO₃, 150° C., microwave

133 8 PdCl₂(^(t)Bu₂PhP)₂, KOAc, 100° C.,

134 4 Same

Example 135N-(4-(3-(2-METHYLPYRIDIN-4-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

A suspension ofN-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (180 mg,0.507 mmol), 2-methylpyridin-4-ylboronic acid (278 mg, 2.03 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (41.4 mg, 0.051 mmol), and sodium carbonate(323 mg, 3.04 mmol) in 1,4-dioxane (3 mL) and water (2 mL) was spargedwith argon for 5 min, then heated to 100° C. for 2 h. The reactionmixture was partitioned between EtOAc and 1M NaOH. The aqueous layer wasextracted with EtOAc (2×) and the combined organics was dried overNa₂SO₄ and concentrated. The crude material was absorbed on Silica geland purified by chromatography through a Redi-Sep pre-packed silica gelcolumn (40 g), eluting with a gradient of 0% to 70% EtOAc in hexane, toprovideN-(4-(3-(2-methylpyridin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amineas white solid. MS (ESI, pos. ion) m/z: 412.0 (M+1). IC50 (uM) +++++.

Example 1363-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)-3-FLUOROPHENOXY)PYRAZIN-2-YL)CYCLOHEX-2-ENONE

A mixture ofN-(4-(3-chloropyrazin-2-yloxy)-2-fluorophenyl)benzo[d]thiazol-2-amine(2098 mg, 5.63 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1000mg, 4.50 mmol), dichlorobis(triphenylphosphine)palladium(ii) (316 mg,0.450 mmol), and sodium carbonate (1432 mg, 13.51 mmol) in DME/H₂O/EtOH(7:3:2, 36 ml) was heated to 140° C. for 3 h. Water (100 ml) was addedand the reaction mixture was extracted with EtAOc (3×100 ml). Thecombined organic layers were washed with brine and dried over sodiumsulfate. Filtration and concentration under reduced pressure afforded3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enone.MS (ESI, pos. ion) m/z: 433.0 (M+1). IC50 (uM) +++++.

Example 137(RAC)-3-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)-3-FLUOROPHENOXY)PYRAZIN-2-YL)CYCLOHEX-2-ENOL

Sodium tetrahydroborate (157 mg, 4.16 mmol) was added to a suspension of3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enone(600 mg, 1.387 mmol) in MeOH (20 ml) at RT. The mixture was stirred atRT for 1 h, and was then cooled in an ice-water bath. Saturated aqueousammonium chloride (5 ml) was added along with distilled water (100 ml).The resulting mixture was extracted with EtOAc (2×100 ml), and thecombined organic layers were washed with brine and dried over sodiumsulfate. Filtration and concentration under reduced pressure, followedby flash chromatography on silica gel (30% to 60% EtOAc in hexanes)afforded(rac)-3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enolas a white solid. MS (ESI, pos. ion) m/z: 435.0 (M+1). IC50 (uM) +++++.

TABLE (IVA) EXAMPLES 138 TO 159 ARE TABULATED BELOW: IC50 Ex # Structure(uM) IUPAC names MS 138

+++ N-(4-(3-(6- morpholinopyridin- 3-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 483 139

+++ N-(4-(3-(4- morpholinophenyl) pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 482 140

+++++ N-(4-(3-(6- methylpyridin-3- yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 412 141

++++ N-(4-(3-(1H- pyrrolo[2,3- b]pyridin-5- yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 437 142

+++++ 5-(3-(4- (benzo[d]thiazol- 2- ylamino)phenoxy) pyrazin-2-yl)picolinonitrile 423 143

+++++ N-(4-(3- (pyrimidin-5- yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 399 144

+++++ N-(4-(3-(2- methoxypyrimidin- 5-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 429 145

+++++ N-(4-(3-(6- chloropyridin-3- yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 432 146

++++ (5-(3-(4- (benzo[d]thiazol- 2- ylamino)phenoxy) pyrazin-2-yl)pyridin-2- yl)methanol 428 147

++++ N-(4-(3- (quinolin-5- yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 448 148

+++++ N-(4-(3-(pyridin- 3-yl)pyrazin-2- yloxy)phenyl) benzo[d]thiazol-2-amine 398 149

+++++ N-(4-(3-(3- methoxypyridin- 4-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 428 150

++++ N-(4-(3-(3- methoxyphenyl) pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 427 151

++++ 7-fluoro-N-(4-(3- (2- methoxypyridin- 3-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 446 152

+++++ N-(4-(3-(2- methoxypyridin- 4-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 428 153

++++ 6-fluoro-N-(4-(3- (2- methoxypyridin- 3-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 446 154

++++ 5-fluoro-N-(4-(3- (2- methoxypyridin- 3-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 446 155

+++++ N-(4-(3-(2- methoxypyridin- 3-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 428 156

++++ N-(4-(3-(5- methoxypyridin-3- yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2-amine 428 157

++++ N-(2-fluoro-4-(3- (2- methoxypyridin- 3-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 446 158

++++ N-(2-fluoro-4-(3- (2-fluoropyridin- 4-yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2- amine 434 159

+++++ tert-butyl 4-(3- (4- (benzo[d]thiazol- 2-ylamino)-3-fluorophenoxy) pyrazin-2-yl)-5,6- dihydropyridine- 1(2H)- carboxylate520

TABLE (IVB) PREPARATION OF EXAMPLES 138 TO 159 ARE TABULATED BELOW: HowDifferent Synthetic from Main Ex # Scheme Route Reagent Difference 138 9Same

139 9 Same

140 9 Same

141 9 Same

142 9 Same

143 9 Same

144 9 Same

145 9 Same

146 9 Same

147 9 Same

148 9 Same

149 9 KOAc, A- Phos, 130° C.

150 9 Same

151 9 Same

152 9 Same

153 9 Same

154 9 Same

155 9 K₃PO₄, A- Phos, 150° C., microwave

156 9 K₃PO₄, A- Phos, 150° C., microwave

157 9 (Ph₃P)₂PdCl₂, 120° C., microwave

158 9 (Ph₃P)₂PdCl₂, 100° C., microwave

159 9 (Ph₃P)₂PdCl₂, 140° C., microwave

General Procedure:

Into 8 mL vial was added alcohol (4 eq., 2 mmol), CsF (304 mg, 4 eq., 2mmol) and a solution of(1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone(175 mg, 500 umol) in 6 mL of anhydrous DMSO. The vial was capped andheated at 80° C. for 12 h. The reaction mixture was cooled to roomtemperature and filtered to remove insoluble material. The compoundswere purified by HPLC.

TABLE (VA) EXAMPLES 160 TO 180 ARE TABULATED BELOW: IC50 MS Ex #Structure (uM) IUPAC names (M + 1) 160

+ (1H-benzo[d]imidazol-2-yl)(4- (3-methoxypyrazin-2-yloxy)phenyl)methanone 347 161

+ (1H-benzo[d]imidazol-2-yl)(4- (3-isopropoxypyrazin-2-yloxy)phenyl)methanone 375 162

+ (1H-benzo[d]imidazol-2-yl)(4- (3-isobutoxypyrazin-2-yloxy)phenyl)methanone 389 163

++ (1H-benzo[d]imidazol-2-yl)(4- (3- (cyclopropylmethoxy)pyrazin-2-yloxy)phenyl)methanone 387 164

++ (1H-benzo[d]imidazol-2-yl)(4- (3-(2,2,2- trifluoroethoxy)pyrazin-2-yloxy)phenyl)methanone 415 165

++ (1H-benzo[d]imidazol-2-yl)(4- (3-(2-methoxyethoxy)pyrazin-2-yloxy)phenyl)methanone 391 166

++++ (1H-benzo[d]imidazol-2-yl)(4- (3-(pyridin-2- ylmethoxy)pyrazin-2-yloxy)phenyl)methanone 424 167

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-phenoxypyrazin-2-yloxy)phenyl)methanone 409 168

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-(pyridin-3-yloxy)pyrazin-2-yloxy)phenyl)methanone 410 169

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-(but-2-ynyloxy)pyrazin-2-yloxy)phenyl)methanone 385 170

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-(2-(4-methylthiazol-5-yl)ethoxy)pyrazin-2- yloxy)phenyl)methanone 458 171

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-((tetrahydrofuran-3-yl)methoxy)pyrazin-2- yloxy)phenyl)methanone 417 172

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-(2- morpholinoethoxy)pyrazin-2-yloxy)phenyl)methanone 446 173

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-(2-(pyrrolidin-1-yl)ethoxy)pyrazin-2- yloxy)phenyl)methanone 430 174

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-(2- (dimethylamino)ethoxy)pyrazin-2-yloxy)phenyl methanone 404 175

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-(2-(1-methylpyrrolidin-2-yl)ethoxy)pyrazin-2- yloxy)phenyl)methanone 444 176

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-(pyridin-4- ylmethoxy)pyrazin-2-yloxy)phenyl)methanone 424 177

++++ (1H-benzo[d]imidazol-2-yl)(4- (3-(2-(pyridin-2-yl)ethoxy)pyrazin-2- yloxy)phenyl)methanone 438 178

++++ (1H-benzo[d]imidazol-2-yl)(4- (3-(3-(pyridin-3-yl)propoxy)pyrazin-2- yloxy)phenyl)methanone 452 179

+++ (1H-benzo[d]imidazol-2-yl)(4- (3-(pyridin-3- ylmethoxy)pyrazin-2-yloxy)phenyl)methanone 424 180

+ (1H-benzo[d]imidazol-2-yl)(4- (3-propoxypyrazin-2-yloxy)phenyl)methanone 375

TABLE (VB) PREPARATION OF EXAMPLES 160 TO 180 ARE TABULATED BELOW:Synthetic How Different from Reagent Ex # Scheme Main Route Difference160 10 Same

161 10 Same

162 10 Same

163 10 Same

164 10 Same

165 10 Same

166 10 Same

167 10 Same

168 10 Same

169 10 Same

170 10 Same

171 10 Same

172 10 Same

173 10 Same

174 10 Same

175 10 Same

176 10 Same

177 10 Same

178 10 Same

179 10 Same

180 10 Same

Example 181(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(3,6-DIHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

A clear 150 ml pressure tube was charged with(1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone(1.00 g, 2.85mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.396 g, 11.40 mmol),Bis-[4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine]palladiumdichloride (0.101 g, 0.143 mmol), potassium acetate (0.616 g, 6.27mmol), dioxane (9 mL) and water (1.000 mL). The reaction flask wasflushed with nitrogen and capped. The reaction was heated to 100° C. for16 hours. The reaction was then cooled down to RT and partitioned withethyl acetate (50 ml) and water (50 ml). The organic layer was washed(2×) with an aqueous saturated solution of sodium bicarbonate, then withwater and then brine. The organic layer was then dried with sodiumsulfate and then filtered. The volatile were reduced to a smaller volumeand the solid that precipitated out was filtered off. The cake obtainedwas suspended in hot MeOH, filtered and dried to give(1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanoneas a yellow solid. [M+1] 398.9

STEP 2.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANOL

A 1 L heavy wall vessel equipped with a magnetic stir bar flask wascharged with(1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone(1.00 g, 2.26 mmol), ammonium formate (3.16 g, 50 mmol), THF (125 mL)and MeOH (125 mL). Nitrogen was bubbled into the mixture for 15 mins.The mixture was kept under nitrogen and treated with Pd/C (0.267 g,0.251 mmol). The vessel was capped and the reaction was stirred at 75°C. After 5 hours, the reaction was cooled down to RT. An aliquot wasanalyzed via LC-MS showed the reaction was incomplete. The reaction wasfiltered through celite and the filtrate was transferred back to thereaction vessel. An additional 4.15 g of ammonium formate and 0.350 of10% Pd/C was added to the reaction under nitrogen. The vessel cappedagain and heated to 75° C. overnight. The reaction was cooled down andfiltered through a pad of celite. The filtrate was reduced under vacuum.The residue obtained was portioned with DCM and water. The organic layerwas washed (2×) with an aqueous saturated solution of sodiumbicarbonate, then with water and then brine. The organic layer was thendried with sodium sulfate reduced. The volatiles were removed undervacuum. The residue obtained was triturated with hot MeOH, filtered anddried in a vacuum oven to give(1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanolas a white solid. [M+1] 402.9.

STEP 3.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

A mixture of(1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanol(0.50 g, 1.24 mmol) in chloroform (7.5 mL) and acetone (4.00 mL) undernitrogen was treated with was treated with manganese dioxide (0.504 g,6.21 mmol) in one portion. The reaction was heated to 50° C. After 40minutes, the reaction was filtered through a pad of Celite™. Thefiltrate was washed (2×) with an aqueous saturated solution of sodiumbicarbonate, with water and then brine. The organic layer was then driedwith sodium sulfate and purified by column chromatography on silica gelusing a gradient of 30 to 80% ethyl acetate in hexanes. The purefractions were reduced under vacuum and the solid obtained was slurriedin 1:1 EtOAc:ether, filtered and dried under vacuum to give(1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanoneas a white solid. MS (ESI, pos. ion) m/z: 400.9 (M+1). IC50 (uM) +++++.

TABLE (VIA) EXAMPLES 182 TO 185 ARE TABULATED BELOW: IC50 Ex # Structure(uM) IUPAC names MS 182

+++++ (1H-imidazol[4,5- b]pyridin-2-yl)(4-(3- (tetrahydro-2H-pyran-4-yl)pyrazin-2- yloxy)phenyl)methanone 401.9 183

+++++ (6-fluoro-1H- benzo[d]imidazol-2- yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin- 2- yloxy)phenyl)methanone 419 184

+++++ (1-methyl-1H- benzo[d]imidazol-2- yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin- 2- yloxy)phenyl)methanone 415 185

+++++ (6-fluoro-1-methyl-1H- benzo[d]imidazol-2- yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin- 2- yloxy)phenyl)methanone and (5-fluoro-1-methyl-1H- benzo[d]imidazol-2- yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin- 2- yloxy)phenyl)methanone 433

TABLE (VIB) PREPARATION OF EXAMPLES 182 TO 185 ARE TABULATED BELOW:Synthetic How Different from Ex # Scheme Main Route Reagent Difference182 11 Same

183 11 Same

184 4 Same

185 4 Same

Example 1861H-BENZIMIDAZOL-2-YL(4-4-((3-(TETRAHYDRO-2H-PYRAN-3-YL)-2-PYRAZINYL)OXY)PHENYL)METHANONESTEP 1: 3,4-DIHYDRO-2H-PYRAN-5-YL TRIFLUOROMETHANESULFONATE

Diisopropylamine (1.7 mL, 12.0 mmol) was taken up in 30 mL of THF andchilled to −78° C. N-butyllithium (4.8 mL, 2.5 M in hexanes) was addedto the mixture. After 5 minutes, dihydro-2H-pyran-3(4H)-one (1.0 g, 10.0mmol) was added slowly in 8 mL of THF. After 10 minutes,N-phenyltriflimide (3.9 g, 11 mmol) was added slowly in 8 mL of THF.After 15 minutes, the mixture was warmed to rt. The mixture was stirredfor 1.5 hours and quenched with 30 mL of aq NaHCO₃. The mixture was thenextracted twice with 35 mL of ether and the combined organic extractswere washed with 25 mL of brine and dried over MgSO₄. Filtration andconcentration under reduced pressure, followed by flash chromatographyon silica gel (2.5% to 20% EtOAc/hexanes) afforded3,4-dihydro-2H-pyran-5-yl trifluoromethanesulfonate.

STEP 2:5-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-3,4-DIHYDRO-2H-PYRAN

3,4-Dihydro-2H-pyran-5-yl trifluoromethanesulfonate (0.66 g, 2.8 mmol),bis(pinacolato)diboron (0.79 g, 3.1 mmol), potassium acetate (0.84 g,8.5 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium (ii)dichloride dichloromethane complex (0.070 g, 0.085 mmol) were taken upin 10 mL of dioxane in a sealable tube. The mixture was purged withnitrogen and the tube was sealed. The tube was then heated to 80° C.After 12 hours, the mixture was cooled to rt. The mixture was dilutedwith 40 mL of EtOAc and washed with 10 mL of water and 10 mL of brine,then dried over MgSO₄. Filtration and concentration under reducedpressure, followed by flash chromatography on silica gel (1% to 10%EtOAc/hexanes) afforded5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyran.

STEP 3:1H-BENZIMIDAZOL-2-YL(4-((3-(5,6-DIHYDRO-2H-PYRAN-3-YL)-2-PYRAZINYL)OXY)PHENYL)METHANONE

H-benzimidazol-2-yl (44(3-chloro-2-pyrazinyl)oxy)phenyl)methanone (0.46g, 1.3 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyran(0.39 g, 1.9 mmol), potassium acetate (0.99 g, 10.0 mmol), andbis[di-tert-butyl(phenyl)phosphane]dichloropalladium (0.062 g, 0.099mmol) were taken up in 16 mL of 3:1 MeCN:water. The mixture as purgedwith nitrogen and the reaction was heated to 100° C. After 48 hours, themixture was diluted with 20 mL of water and extracted three times with20 mL of 9:1 chloroform/isopropanol. The combined organic extracts weredried over MgSO₄. Filtration and concentration under reduced pressure,followed by flash chromatography on silica gel (0 to 2%MeOH/dichloromethane) afforded1H-benzimidazol-2-yl(4-(3-(5,6-dihydro-2H-pyran-3-yl)-2-pyrazinyl)oxy)phenyl)methanone.

STEP 4:1H-BENZIMIDAZOL-2-YL(4-((3-(TETRAHYDRO-2H-PYRAN-3-YL)-2-PYRAZINYL)OXY)PHENYL)METHANOL

1H-Benzimidazol-2-yl(4-((3-(5,6-dihydro-2H-pyran-3-yl)-2-pyrazinyl)oxy)phenyl)methanone(0.20 g, 0.50 mmol) was suspended in 15 mL of EtOAc in a pressure tube.Palladium on carbon, 10% (0.20 g) was added. The mixture washydrogenated at 50 psi. After 24 hours, the mixture was filtered throughcelite and eluted with 50 mL of 9:1 chloroform:isopropanol. The productwas taken up in 10 mL of dichloromethane. Manganese dioxide (0.58 g, 6.7mmol) was added. After 1 h, the mixture was filtered through celite andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel (0 to 2% MeOH/dichloromethane) affording1H-benzimidazol-2-yl(4-((3-(tetrahydro-2H-pyran-3-yl)-2-pyrazinyl)oxy)phenyl)methanone.MS (ESI, pos. ion) m/z: 401 (M+1). IC50 (uM) +++++.

Example 1871H-BENZIMIDAZOL-2-YL(4-((3-(4-METHOXY-1-CYCLOHEXEN-1-YL)-2-PYRAZINYL)OXY)PHENYL)METHANONE

STEP 1. 4-METHOXYCYCLOHEXANONE

4-Methoxycyclohexanol (2.0 g, 15.0 mmol) was taken up in 150 mL of DCM.Pyridinium chlorochromate (5.0 g, 23.0 mmol) was added. After 60 hours,the mixture was filtered through a plug of Florisil and concentratedunder reduced pressure. The residue was taken up in 50 mL of ether andfiltered through a plug of silica gel. The solvent was removed underreduced pressure, affording 4-methoxycyclohexanone as a light yellowoil.

STEP 2. 4-METHOXY-1-CYCLOHEXEN-1-YL TRIFLUOROMETHANESULFONATE

Diisopropylamine (1.5 mL, 10.0 mmol) was taken up in 25 mL of THF andchilled to −78° C. Butyllithium, 2.5 M in hexanes (4.1 mL, 10.0 mmol)was added slowly. After 5 minutes, 4-methoxycyclohexanone (1.1 g, 8.6mmol) was added slowly in 7 mL of THF. After 10 minutes,n-phenyltriflimide (3.4 g, 9.4 mmol) was added slowly in 7 mL of THF.After 15 minutes, the mixture was warmed to room temperature. Themixture was stirred for 90 minutes, then quenched with 25 mL of aqNH₄Cl. The mixture was then diluted with 20 mL of water and extractedtwice with 30 mL of ether. The combined organic extracts were dried overMgSO₄. Filtration and concentration under reduced pressure, followed byflash chromatography on silica gel (1% to 10% EtOAc/hexanes) afforded4-methoxy-1-cyclohexen-1-yl trifluoromethanesulfonate as a clear oil.

STEP 3.2-(4-METHOXY-1-CYCLOHEXEN-1-YL)-4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLANE

4-methoxy-1-cyclohexen-1-yl trifluoromethanesulfonate (1.3 g, 5.0 mmol),bis(pinacolato)diboron (1.5 g, 6.0 mmol), potassium acetate (1.5 g, 15.0mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium (ii)dichloride dichloromethane complex (0.12 g, 0.15 mmol) were taken up in25 mL of dioxane. The mixture was purged with nitrogen and heated to 80°C. After 12 hours, the mixture was cooled to room temperature anddiluted with 50 mL of EtOAc. The mixture was washed with 10 mL of waterand 10 mL of brine, then dried over MgSO₄. Filtration and concentrationunder reduced pressure, followed by flash chromatography on silica gel(1.5 to 10% EtOAc/hexanes) afforded2-(4-methoxy-1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a clear oil.

STEP 4.1H-BENZIMIDAZOL-2-YL(4-((3-(4-METHOXY-1-CYCLOHEXEN-1-YL)-2-PYRAZINYL)OXY)PHENYL)METHANONE

(1H-Benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone(1.0 g, 2.8 mmol), potassium acetate (2.1 g, 21.0 mmol),2-(4-methoxy-1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.88 g, 3.7 mmol), and bis[di-tert-butyl(phenyl)phosphane]dichloropalladium (0.13 g, 0.213 mmol) were taken up in 40 mLof 3:1 MeCN:water. The mixture was purged with nitrogen and heated to100° C. After 12 hours, the mixture was cooled to room temperature anddiluted with 40 mL of water. The mixture was extracted twice with 30 mLof 9:1 chloroform:IPA. The combined organic extracts were dried overMgSO₄. Filtration and concentration under reduced pressure, followed byflash chromatography on silica gel (0.5 to 5% MeOH/DCM) afforded1H-Benzimidazol-2-yl(4-((3-(4-methoxy-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)phenyl)methanoneas a yellow solid. MS (ESI, pos. ion) m/z: 427.1 (M+1). IC50 (uM) +++++.

Example 1881H-BENZIMIDAZOL-2-YL(4-((3-(CIS-4-HYDROXYCYCLOHEXYL)-2-PYRAZINYL)OXY)PHENYL)METHANONEAND1H-BENZIMIDAZOL-2-YL(4-((3-(TRANS-4-HYDROXYCYCLOHEXYL)-2-PYRAZINYL)OXY)PHENYL)METHANONESTEP 1. 4-((TERT-BUTYL(DIMETHYL)SILYL)OXY)-1-CYCLOHEXEN-1-YLTRIFLUOROMETHANESULFONATE

Diisopropylamine (1.7 mL, 12.0 mmol) was taken up in 30 mL of THF andchilled to −78° C. N-butyllithium, (4.8 mL, 2.5 M in heaxnes) was added.After 5 minutes, 4-((tert-butyl(dimethyl)silyl)oxy)cyclohexanone (2.3 g,10.0 mmol) was added dropwise in 8 mL of THF. After 10 minutes,n-phenyltriflimide (4.0 g, 11.0 mmol) was added dropwise in 8 mL of THF.After 10 minutes, the mixture was warmed to rt and stirred for 12 hours.The mixture was quenched with 40 mL of aq NH₄Cl and extracted twice with40 mL of EtOAc. The combined organic extracts were washed with 40 mL ofbrine and dried over MgSO₄. Filtration and concentration under reducedpressure, followed by flash chromatography on silica gel (0 to 5%EtOAc/hexanes) afforded4-((tert-butyl(dimethyl)silyl)oxy)-1-cyclohexen-1-yltrifluoromethanesulfonate.

STEP 2.((4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-3-CYCLOHEXEN-1-YL)OXY)SILANE

4-((tert-butyl(dimethyl)silyl)oxy)-1-cyclohexen-1-yltrifluoromethanesulfonate (2.6 g, 7.2 mmol), bis(pinacolato)diboron (2.2g, 8.7 mmol), potassium acetate (5.3 g, 54.0 mmol), and1,1′-bis(diphenylphosphino)ferrocene-palladium (ii) dichloridedichloromethane complex (0.18 g, 0.22 mmol) were taken up in 35 mL ofdioxane. The mixture was purged with nitrogen and heated to 80° C. After12 hours, the mixture was diluted with 75 mL of EtOAc and 75 mL ofwater. The mixture was partitioned and the aqueous portion was extractedwith 75 mL of EtOAc. The combined organic extracts were washed with 75mL of brine and dried over MgSO₄. Filtration and concentration underreduced pressure, followed by flash chromatography on silica gel (0.5%to 2.5 EtOAc/hexanes) afforded((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexen-1-yl)oxy)silane.

STEP 3.1H-BENZIMIDAZOL-2-YL(4-((3-(4-((TERT-BUTYL(DIMETHYL)SILYL)OXY)-1-CYCLOHEXEN-1-YL)-2-PYRAZINYL)OXY)PHENYL)METHANONE

1H-benzimidazol-2-yl(4-((3-chloro-2-pyrazinyl)oxy)phenyl)methanone (0.50g,

1.4 mmol),((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-cyclohexen-1-yl)oxy)silane(0.68 g, 2.0 mmol), potassium acetate (1.0 g, 11.0 mmol), andbis[di-tert-butyl(phenyl)phosphane]dichloropalladium (0.066 g, 0.11mmol) were taken up in 24 mL of 3:1 MeCN:water. The mixture was purgedwith nitrogen and heated to 100° C. After 18 hours, the mixture wasdiluted with 30 mL of water and extracted three times with 25 mL of 9:1chloroform:isopropanol. The combined organic extracts were dried overMgSO₄. Filtration and concentration under reduced pressure, followed byflash chromatography on silica gel (5% to 25% EtOAc/hexanes) afforded1H-benzimidazol-2-yl(4-((3-(4-((tert-butyl(dimethyl)silyl)oxy)-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)phenyl)methanone.

STEP 4.1H-BENZIMIDAZOL-2-YL(4-((3-(4-HYDROXY-1-CYCLOHEXEN-1-YL)-2-PYRAZINYL)OXY)PHENYL)METHANONE

H-benzimidazol-2-yl(4-((3-(4-((tert-butyl(dimethyl)silyl)oxy)-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)phenyl)methanone(0.15 g, 0.28 mmol) was taken up in 5 mL of THF. Tetrabutylammoniumfluoride (0.34 mL, 1.0 M in THF) was added to the mixture. The mixturewas stirred for 60 hours. The mixture was diluted with 10 mL of aqNH₄Cl. The mixture was extracted twice with 10 mL of EtOAc and thecombined organic extracts were dried over MgSO₄. Filtration andconcentration under reduced pressure, followed by flash chromatographyon silica gel (0 to 3% MeOH/dichloromethane) afforded1H-benzimidazol-2-yl(4-((3-(4-hydroxy-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)phenyl)methanone.

STEP 5.1H-BENZIMIDAZOL-2-YL(4-((3-(CIS-4-HYDROXYCYCLOHEXYL)-2-PYRAZINYL)OXY)PHENYL)METHANONEAND1H-BENZIMIDAZOL-2-YL(4-((3-(TRANS-4-HYDROXYCYCLOHEXYL)-2-PYRAZINYL)OXY)PHENYL)METHANONE

1H-benzimidazol-2-yl(4-((3-(4-hydroxy-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)-phenyl)methanone(0.27 g, 0.66 mmol) was suspended in 20 mL of EtOAc in a pressure tube.Palladium on carbon, 10% (0.20 g) was added. The mixture washydrogenated at 50 psi. After 60 hours the mixture was filtered througha plug of celite and eluted with 50 mL of 9:1 chloroform:isopropanol.The solvent was removed under reduced pressure. The residue was taken upin 50 mL of dichloromethane. The mixture was sonicated for 5 minutes todissolve the starting material. Manganese dioxide (0.84 g, 9.7 mmol) wasadded. After 2 hours, the mixture was filtered through celite, elutedwith 50 mL of 9:1 chloroform/isopropanol, and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel(0 to 2.5% MeOH/dichloromethane). Two products of identical mass thatco-eluted were isolated. The mixture was further purified by preparatoryHPLC (Phenomenex Gemini column [C18, 10 micro, 150×30 mm] 15% to 100%MeCN/water over 20 min at 35 mL/min) affording1H-benzimidazol-2-yl(4-((3-(cis-4-hydroxycyclohexyl)-2-pyrazinyl)oxy)phenyl)methanone(MS m/z: 401(M+1) and1H-benzimidazol-2-yl(4-((3-(trans-4-hydroxycyclohexyl)-2-pyrazinyl)oxy)-phenyl)methanone.MS (ESI, pos. ion) m/z: 401 (M+1). IC50 (uM) +++++.

STEP 1: 3-OXOCYCLOHEX-1-ENYL TRIFLUOROMETHANESULFONATE

A 1.0M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran(102 mL, 102 mmol) was added dropwise to a solution ofcyclohexane-1,3-dione (11.4 g, 102 mmol) in THF (200 ml) at −50° C. Themixture was stirred at −50° C. for 15 min and trifluoromethanesulfonicanhydride (30.1 g, 107 mmol) was added through an addition funnel. Aftercompletion of the addition the reaction mixture was allowed to slowlywarm to RT. The reaction mixture was then cooled to −30° C., and 200 mLof saturated aqueous sodium bicarbonate was added slowly. The solventwas removed under reduced pressure and the remaining aqueous layer wasextracted with EtOAc (2×400 ml). The combined organic layers were washedwith brine and dried over sodium sulfate. Filtration and concentrationunder reduced pressure, followed by flash chromatography on silica gel(0% to 10% EtOAc in hexanes) afforded 3-oxocyclohex-1-enyltrifluoromethanesulfonate as a yellow oil. MS (ESI, pos. ion) m/z: 245.0(M+1).

STEP 2. 3-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)CYCLOHEX-2-ENONE

3-Oxocyclohex-1-enyl trifluoromethanesulfonate (9 g, 36.9 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (10.30 g,40.5 mmol), and potassium acetate (7.23 g, 73.7 mmol) were suspended in100 ml dioxane. Argon was bubbled through the reaction mixture for 5minutes, and dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(ii) (2.107 g, 2.58 mmol) was added. The mixture was stirred at 80° C.for 3 h, cooled to RT, and concentrated under reduced pressure. Water(300 ml) was added and the mixture was extracted with EtOAc (3×200 ml).The combined organic layer were washed by brine and dried over sodiumsulfate. Filtration and concentration under reduced pressure, followedby flash chromatography on silica gel (0% to 20% EtOAc in hexanes)afforded 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enoneas colorless crystals.

STEP 3. 3-(3-FLUOROPYRAZIN-2-YL)CYCLOHEX-2-ENONE

2-Fluoro-3-iodopyrazine (2.5 g, 11.16 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (3.10 g,13.95 mmol), and sodium carbonate (3.55 g, 33.5 mmol) were suspended inDME (20 ml) and distilled water (5 ml). Argon was bubbled through theresulting mixture for 3 minutes, anddichlorobis(triphenylphosphino)palladium (ii) (0.431 g, 0.614 mmol) wasadded. The resulting mixture was stirred at 80° C. for 16 hours, thereaction was cooled to RT, and water (200 ml) was added. The resultingmixture was concentrated under reduced pressure and was extracted withEtOAc (3×200 ml). The combined organic layers were washed with brine anddried over sodium sulfate. Filtration and concentration under reducedpressure, followed by flash chromatography on silica gel (0% to 20%EtOAc in hexanes) afforded 3-(3-fluoropyrazin-2-yl)cyclohex-2-enone as alight yellow solid. MS (ESI, pos. ion) m/z: 193.1 (M+1).

STEP 4. (RAC)-CIS-3-(3-FLUOROPYRAZIN-2-YL)CYCLOHEXANOL AND(RAC)-TRANS-3-(3-FLUOROPYRAZIN-2-YL)CYCLOHEXANOL

Sodium borohydride (295 mg, 7.80 mmol) was added was added portion wiseto a solution of 3-(3-fluoropyrazin-2-yl)cyclohex-2-enone (500 mg, 2.60mmol) in MeOH (15 ml) at RT. After completion of the addition thereaction mixture was stirred at RT for 30 minutes. It was then cooled inan ice-water bath, saturated aqueous ammonium chloride (25 ml) was addeddropwise, and the resulting mixture was extracted with EtOAc (2×100 ml).The combined organic layers were washed with brine and dried over sodiumsulfate. Filtration and concentration under reduced pressure, followedby flash chromatography on silica gel (0% to 20% EtOAc in hexanes)afforded (rac)-cis-3-(3-fluoropyrazin-2-yl)cyclohexanol and(rac)-trans-3-(3-fluoropyrazin-2-yl)cyclohexanol as colorless oils. MS(ESI, pos. ion) m/z: 197.0 (M+1) and MS (ESI, pos. ion) m/z: 197.0(M+1), respectively. IC50 (uM) +++++.

Example 189(RAC)-CIS-(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(3-HYDROXYCYCLOHEXYL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

A mixture of (rac)-cis-3-(3-fluoropyrazin-2-yl)cyclohexanol (140 mg,0.713 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (340mg, 1.427 mmol), and cesium carbonate (465 mg, 1.427 mmol) in NMP (1.8ml) was heated in a Biotage™ microwave reactor at 180° C. for 45 min.The mixture was partitioned between H₂O(10 ml) and CH₂Cl₂ (20 ml), thelayers were separated, and the aqueous layer was extracted with CH₂Cl₂(3×20 ml). The combined organic layers were dried (MgSO₄), concentratedunder reduced pressure, and the resulting brown oil was purified byreversed phase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to95% H₂O/MeCN, 0.1% TFA). The product containing fractions were combined,neutralized by the addition of solid Na₂CO₃, and extracted with CH₂Cl₂(3×20 mL). The combined organic layers were dried (MgSO₄) andconcentrated under reduced pressure to deliver(rac)-cis-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanoneas a brown foam. MS (ESI, pos. ion) m/z: 415.0 (M+1). IC50 (uM) +++++.

Example 190(RAC)-TRANS-(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(3-HYDROXYCYCLOHEXYL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

A mixture of (rac)-trans-3-(3-fluoropyrazin-2-yl)cyclohexanol (106 mg,0.540 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (257mg, 1.080 mmol), and cesium carbonate (352 mg, 1.080 mmol) was heated ina Biotage™ microwave reactor at 150° C. for 30 min. The mixture waspartitioned between H₂O (10 ml) and CH₂Cl₂ (20 ml), the layers wereseparated, and the aqueous layer was extracted with CH₂Cl₂ (3×20 ml).The combined organic layers were dried (MgSO₄), concentrated underreduced pressure, and the resulting brown oil was purified by reversedphase HPLC (Gilson Gemini-NX 10u C18 110A, 100×50.0 mm, 10% to 95%H₂O/MeCN, 0.1% TFA). The product containing fractions were combined,neutralized by the addition of solid Na₂CO₃, and extracted with CH₂Cl₂(3×20 mL). The combined organic layers were dried (MgSO₄) andconcentrated under reduced pressure to deliver(rac)-trans-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanoneas a light yellow solid. MS (ESI, pos. ion) m/z: 415.1 (M+1). IC50 (uM)+++++.

TABLE (VIIA) EXAMPLES 191 TO 192 TABULATED BELOW: IC50 Ex # Structure(uM) IUPAC names MS 191

+++++ (rac)-cis-3-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)cyclohexanol 419 192

+++++ (rac)-trans-3-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2- yl)cyclohexanol 419

TABLE (VIIB) PREPARATION OF EXAMPLES 191 TO 192 ARE TABULATED BELOW: HowFifferent Ex Synthetic from # Scheme Main Route Reagent Difference 191 3Same

192 4 Same

Example 193N-(4-(3-(TETRAHYDRO-2H-PYRAN-3-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

STEP 1. TETRAHYDRO-2H-PYRAN-3-OL

To a stirred solution of 3,4-dihydro-2H-pyran (5.42 mL, 59.4 mmol) inTHF (100 mL) at 0° C. under a nitrogen atmosphere was added boranetetrahydrofuran complex, (29.7 mL, 29.7 mmol, 1.0 M in THF) via syringe.The reaction mixture was stirred at 0° C. for 3 h before a mixture of 5M aqueous sodium hydroxide (40 mL) and 30% aqueous hydrogen peroxide (20mL) was added. The reaction mixture was warmed to room temperature andstirred for 3 h. Sat. aqueous sodium bicarbonate was added, and themixture was extracted with EtOAc (2×). The combined organic layers werewashed with sat. aqueous sodium chloride, dried over magnesium sulfate,filtered, and concentrated in vacuo to give tetrahydro-2H-pyran-3-ol.

STEP 2. DIHYDRO-2H-PYRAN-3(4H)-ONE

To a stirred mixture of pyridinium chlorochromate (11.02 g, 51.1 mmol)and 3 Å molecular sieves (10.00 g) in DCM (100 mL) was added a solutionof tetrahydro-2H-pyran-3-ol (3.48 g, 34.1 mmol) in DCM (100 mL). Thereaction mixture was refluxed for 3 h before being cooled to roomtemperature and partially concentrated in vacuo. The mixture was thendiluted with EtOAc and filtered through Celite. The filtrate wasconcentrated in vacuo and purified by silica gel chromatography to givedihydro-2H-pyran-3(4H)-one.

STEP 3. 5,6-DIHYDRO-2H-PYRAN-3-YL TRIFLUOROMETHANESULFONATE

To a stirred solution of diisopropylamine (3.06 mL, 21.81 mmol) in THF(50 mL) at −78° C. under an argon atmosphere was added butyllithium(8.73 mL, 21.81 mmol, 2.5 M in hexanes). The mixture was stirred for 5min before dihydro-2H-pyran-3(4H)-one (1.82 g, 18.18 mmol) in THF (15mL) was added slowly via syringe. The mixture was stirred for anadditional 15 min before n-phenyltrifluoromethanesulfonimide (7.14 g,20.00 mmol) in THF (15 mL) was added slowly via syringe. The reactionmixture was then stirred at −78° C. for an additional 15 min beforebeing allowed to warm to room temperature and stir for 1 h. Sat. aqueoussodium bicarbonate was added, and the mixture was extracted with EtOAc(2×). The combined organic layers were washed with sat. sodium chloride,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresulting crude oil was purified by silica gel chromatography to give5,6-dihydro-2H-pyran-3-yl trifluoromethanesulfonate.

STEP 4.2-(5,6-DIHYDRO-2H-PYRAN-3-YL)-4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLANE

5,6-Dihydro-2H-pyran-3-yl trifluoromethanesulfonate (1.83 g, 7.88 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.20 g,8.67 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloridepalladium(ii)complex with dichloromethane (0.193 g, 0.236 mmol), andpotassium acetate (1.48 mL, 23.65 mmol) were mixed in dioxane (30 mL)under an argon atmosphere. The reaction mixture was stirred at 80° C.for 17 h. The reaction mixture was cooled to room temperature, dilutedwith water, and extracted with EtOAc. The organic layer was separated,washed with sat. aqueous sodium chloride, dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting crude product waspurified by silica gel chromatography to give2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

STEP 5. 2-CHLORO-3-(5,6-DIHYDRO-2H-PYRAN-3-YL)PYRAZINE

Sodium carbonate (6.48 mL, 12.95 mmol, 2.0 M in water) was added to astirred mixture of 2,3-dichloropyrazine (1.28 mL, 8.63 mmol),2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.91 g, 4.32 mmol), and tetrakis(triphenylphosphine)palladium (0.50 g,0.43 mmol) in dioxane (16 mL) under an argon atmosphere. The reactionmixture was stirred at 80° C. for 16 h before being cooled to roomtemperature and diluted with EtOAc. The mixture was washed with water,washed with sat. sodium chloride, dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting crude product waspurified by silica gel chromatography to give2-chloro-3-(5,6-dihydro-2H-pyran-3-yl)pyrazine. [M+1]=197.0.

STEP 6. 4-(3-(5,6-DIHYDRO-2H-PYRAN-3-YL)PYRAZIN-2-YLOXY)ANILINE

2-Chloro-3-(5,6-dihydro-2H-pyran-3-yl)pyrazine (0.13 g, 0.68 mmol),4-aminophenol (0.15 g, 1.35 mmol), and cesium carbonate (0.44 g, 1.35mmol) were mixed in DMF (2 mL) in a microwave tube. The tube was sealedand placed under a nitrogen atmosphere. The reaction mixture was stirredat 120° C. for 2.5 h. The reaction mixture was cooled to roomtemperature and diluted with water. The resulting precipitate wasfiltered and washed with water to give4-(3-(5,6-dihydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline. [M+1]=270.1.

STEP 7. 4-(3-(TETRAHYDRO-2H-PYRAN-3-YL)PYRAZIN-2-YLOXY)ANILINE

Palladium (10 mg, 0.0094 mmol, 10% wt. on activated carbon) was added toa stirred solution of4-(3-(5,6-dihydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline (0.16 g, 0.59mmol) in THF (3 mL). The reaction mixture was placed under a hydrogenatmosphere (balloon) and stirred at room temperature for 23 h. Thereaction mixture was filtered through Celite, and the filtrate wasconcentrated in vacuo to give4-(3-(tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline. [M+1]=272.1.

STEP 8.N-(4-(3-(TETRAHYDRO-2H-PYRAN-3-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

4-(3-(Tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline (0.082 g, 0.30mmol) and 2-chlorobenzothiazole (0.039 mL, 0.30 mmol) were mixed inisopropyl alcohol (0.50 mL) in a microwave tube. The tube was sealed,and the reaction mixture was refluxed for 2.5 h. The reaction mixturewas cooled to room temperature, diluted with sat. sodium bicarbonate,and extracted with EtOAc (2×). The combined organic layers were washedwith sat. sodium chloride, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting crude product was purified bysilica gel chromatography to giveN-(4-(3-(tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine.MS (ESI, pos. ion) m/z: 405.1 (M+1). IC50 (uM) +++++.

Example 194(RAC)-3-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)CYCLOHEXANONE

STEP 1: (RAC)-3-(3-FLUOROPYRAZIN-2-YL)CYCLOHEXANONE

Pyridine sulfur trioxide (1022 mg, 6.42 mmol) was added to a mixture of(rac)-3-(3-fluoropyrazin-2-yl)cyclohexanone (535 mg, 2.75 mmol) andtriethylamine (975 mg, 9.63 mmol) in DCM (10 ml) and DMSO (20 ml) at 0°C. After 30 min water (100 ml) was added and the resulting mixture wasextracted with DCM (3×50 ml). The organic layer was washed with waterand brine and dried over sodium sulfate. Filtration and concentrationunder reduced pressure afforded(rac)-3-(3-fluoropyrazin-2-yl)cyclohexanone as a white solid. MS (ESI,pos. ion) m/z: 195.1 (M+1).

STEP 1:(RAC)-3-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)CYCLOHEXANONE

Argon was bubbled through a mixture of(rac)3-(3-fluoropyrazin-2-yl)cyclohexanone (250 mg, 1.287 mmol), cesiumcarbonate (1258 mg, 3.86 mmol) and 4-(benzo[d]thiazol-2-ylamino)phenol(468 mg, 1.931 mmol) in NMP (3 ml) for 5 min. The mixture was heated to125° C. for 3 hrs and was then cooled to RT. Distilled water (100 ml)was added and the resulting mixture was extracted with EtOAc (3×50 ml).The organic layer was washed with water and brine and dried over sodiumsulfate. Filtration and concentration under reduced pressure, followedby flash chromatography on silica gel (20% to 50% EtOAc in hexanes)afforded(rac)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanoneas a white solid. MS (ESI, pos. ion) m/z: 417.0 (M+1). IC50 (uM) +++++.

Example 1954-(2-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRIDIN-3-YL)CYCLOHEXANONE

STEP 1. 1,4-DIOXASPIRO[4.5]DECAN-8-OL

Sodium borohydride (4.84 g, 128 mmol) was added in 1 g portions over 30min to a solution of 1,4-dioxaspiro[4.5]decan-8-one (20.0 g, 128 mmol)in MeOH (400 mL) at 0° C. The ice bath was removed and the mixture wasstirred for another 30 min while keeping the temperature of the mixturearound room room temperature. The solvent was then removed in vacuo andthen the resulting solid was suspended in 1:1 Et₂O/EtOAc (400 mL). Theboron salts were dissolved by the addition of sat. aqueous ammoniumchloride, and the resulting layers were separated. The organic layer waswashed with saturated aqueous ammonium chloride (2×), brine (1×), driedover magnesium sulfate, filtered, and concentrated in vacuo to give1,4-dioxaspiro[4.5]decan-8-ol.

STEP 2. 8-BROMO-1,4-DIOXASPIRO[4.5]DECANE

Carbon tetrabromide (11.0 g, 33.2 mmol) was added to a solution oftriphenylphosphine (8.70 g, 33.2 mmol), imidazole (2.47 g, 36.3 mmol),and 1,4-dioxaspiro[4.5]decan-8-ol (5.0 g, 31.6 mmol) in DCM (150 mL)under argon at 0° C. The ice bath was removed and the mixture wasstirred for 24 h at RT. The solvent was removed in vacuo to give an oilthat was purified by silica gel chromatography to give8-Bromo-1,4-dioxaspiro[4.5]decane.

STEP 3. 2-CHLORO-3-(1,4-DIOXASPIRO[4.5]DECAN-8-YL)PYRAZINE

Diisobutylaluminum hydride (0.34 mL, 0.34 mmol, 1.0 M in toluene) andiodine (0.011 g, 0.045 mmol) were added to a mixture of magnesiumturnings (0.34 g, 14.13 mmol) and THF (18 mL) under argon. This mixturewas heated to 65° C. for 45 min, then cooled to RT.8-Bromo-1,4-dioxaspiro[4.5]decane (2.50 g, 11.31 mmol) was added viasyringe and the mixture was then heated to reflux for 1 h to give1,4-dioxaspiro[4.5]decan-8-ylmagnesium bromide.

This solution was added to a mixture of Iron (III) acetylacetonate(0.061 g, 0.17 mmol) and 2,3-dichloropyrazine (514 mg, 3.45 mmol) in THF(10 mL) and NMP (1.5 mL) at 0° C. The reaction mixture was stirred at 0°C. for 1 h, quenched with satd. Aqueous ammonium chloride, and extractedwith EtOAc (3×). The combined organic extracts were dried over magnesiumsulfate, filtered, and concentrated in vacuo. The resulting oil waspurified by silica gel chromatography to give2-chloro-3-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazine. [M+1]=255.1.

STEP 4. 4-(3-CHLOROPYRAZIN-2-YL)CYCLOHEXANONE

2-Chloro-3-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazine (0.29 g, 1.14 mmol)was dissolved in acetone (8 mL) and 1M aqueous hydrochloric acid (1.0mL, 1.0 mmol) was heated to 50° C. for 4 h, then cooled to RT. Theacetone was removed under vacuum and the solution was then diluted withEtOAc. This mixture was transferred to a reparatory funnel and washedwith sat. aqueous sodium bicarbonate (1×), brine (1×), dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingoil was purified by silica gel chromatography to give4-(3-chloropyrazin-2-yl)cyclohexanone.

STEP 5.4-(2-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRIDIN-3-YL)CYCLOHEXANONE

4-(3-Chloropyrazin-2-yl)cyclohexanone (0.10 g, 0.48 mmol),(1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.34 g, 1.42mmol), and cesium carbonate (0.46 mL, 1.42 mmol) were mixed in NMP (1.5mL). The reaction mixture was placed under a nitrogen atmosphere andstirred at 140° C. for 16 h. The reaction mixture was cooled to roomtemperature, diluted with water, and extracted with EtOAc. The organiclayer was washed with 1 M aqueous sodium hydroxide, washed with sat.sodium chloride, dried over magnesium sulfate, and concentrated invacuo. The resulting crude product was purified by silica gelchromatography to give4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cyclohexanone.MS (ESI, pos. ion) m/z: 413.1 (M+1). IC50 (uM) +++++.

Example 196(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-((1S,4S)-4-HYDROXY-4-METHYLCYCLOHEXYL)PYRIDIN-2-YLOXY)PHENYL)METHANONE

STEP 1. (1S,4S)-4-(3-CHLOROPYRAZIN-2-YL)-1-METHYLCYCLOHEXANOL AND(1R,4R)-4-(3-CHLOROPYRAZIN-2-YL)-1-METHYLCYCLOHEXANOL

A suspension of dry cerium(III) chloride (0.20 g, 0.80 mmol) in THF (2mL) was stirred at 40° C. for 2 h under an argon atmosphere. Thesuspension was cooled to −78° C., and methylmagnesium bromide (0.27 mL,0.80 mmol, 3.0 M solution in diethyl ether) was added dropwise viasyringe. The reaction mixture was stirred for 30 min before4-(3-chloropyrazin-2-yl)cyclohexanone (0.14 g, 0.665 mmol) in THF (0.5mL) was added dropwise via syringe. The reaction mixture was stirred at−78° C. for an additional 1.5 h before being quenched with sat. ammoniumchloride and extracted with EtOAc. The organic layer was separated,washed with sat. sodium chloride, dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting crude product waspurified by silica gel chromatography to give(1s,4s)-4-(3-chloropyrazin-2-yl)-1-methylcyclohexanol and(1r,4s)-4-(3-chloropyrazin-2-yl)-1-methylcyclohexanol. [M+1]=227.1 forboth isomers.

STEP 2.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-((1S,4S)-4-HYDROXY-4-METHYLCYCLOHEXYL)PYRIDIN-2-YLOXY)PHENYL)METHANONE

(1s,4s)-4-(3-Chloropyrazin-2-yl)-1-methylcyclohexanol (0.060 g, 0.27mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (019 g, 0.80mmol), and cesium carbonate (0.26 mL, 0.79 mmol) were mixed in NMP (0.7mL) under a nitrogen atmosphere. The reaction mixture was stirred at140° C. for 18 h. The reaction mixture was cooled to room temperature,diluted with water, and extracted with EtOAc (3×). The combined organiclayers were washed with 1 M aqueous sodium hydroxide, washed with sat.sodium chloride, dried over magnesium sulfate, and concentrated invacuo. The resulting crude product was purified by silica gelchromatography (EtOAc/hexanes) to give(1H-benzo[d]imidazol-2-yl)(4-(3-((1s,4s)-4-hydroxy-4-methylcyclohexyl)pyridin-2-yloxy)phenyl)methanone.MS (ESI, pos. ion) m/z: 429.2 (M+1). IC50 (uM) +++++.

Example 197(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-((1R,4R)-4-HYDROXY-4-METHYLCYCLOHEXYL)PYRIDIN-2-YLOXY)PHENYL)METHANONE

(1r,4r)-4-(3-Chloropyrazin-2-yl)-1-methylcyclohexanol (0.05 g, 0.22mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.16 g,0.66 mmol), and cesium carbonate (0.22 g, 0.66 mmol) were mixed in NMP(0.6 mL) under a nitrogen atmosphere. The reaction mixture was stirredat 140° C. for 18 h. The reaction mixture was cooled to roomtemperature, diluted with water, and extracted with EtOAc (3×). Thecombined organic layers were washed with 1 M aqueous sodium hydroxide,washed with sat. sodium chloride, dried over magnesium sulfate, andconcentrated in vacuo. The resulting crude product was purified bysilica gel chromatography to give(1H-benzo[d]imidazol-2-yl)(4-(3-((1r,4r-4-hydroxy-4-methylcyclohexyl)pyridin-2-yloxy)phenyl)methanone.MS (ESI, pos. ion) m/z: 429.2 (M+1). IC50 (uM) +++++.

Example 198(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(OXEPAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1. OXEPAN-4-ONE

To a stirred solution of dihydro-2H-pyran-4(3H)-one (9.23 mL, 100 mmol)and boron trifluoride diethyl etherate (13.80 mL, 110 mmol) in DCM (400mL) at −25° C. was added (trimethylsilyl)diazomethane (54.9 mL, 110mmol, 2.0 m in hexanes) slowly via syringe. The reaction mixture wasstirred at −25° C. for 2.5 h. The reaction mixture was diluted withwater and extracted with DCM. The organic layer was separated, washedwith 10:1 sat. ammonium chloride:ammonium hydroxide, washed with sat.sodium chloride, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting crude product was purified bysilica gel chromatography to give oxepan-4-one.

STEP 2. OXEPAN-4-OL

To a stirred solution of oxepan-4-one (3.40 g, 29.8 mmol) in MeOH (100mL) at 0° C. was added sodium borohydride (1.05 mL, 29.8 mmol). Thereaction mixture was stirred at 0° C. for 30 min. The reaction mixturewas concentrated in vacuo and then partitioned between 1:1 EtOAc/diethylether and sat. ammonium chloride. The organic layer was separated, andthe aqueous layer was extracted once more with 1:1 EtOAc/diethyl ether.The combined organic layers were washed with sat. sodium chloride, driedover magnesium sulfate, filtered, and concentrated in vacuo to giveoxepan-4-ol

STEP 3. 4-IODOOXEPANE

Imidazole (1.58 g, 23.14 mmol), triphenylphosphine (6.07 g, 23.14 mmol),and oxepan-4-ol (2.24 g, 19.28 mmol) were mixed in THF (12 mL) at 0° C.A solution of iodine (5.87 g, 23.14 mmol) in THF (12 mL) was addeddropwise via syringe. The reaction mixture was allowed to warm to roomtemperature and stir for 16 h. The reaction mixture was diluted withEtOAc and washed with 2 M aqueous sodium bisulfite. The aqueous layerwas separated and extracted once more with EtOAc. The combined organiclayers were washed with sat. sodium chloride, dried over magnesiumsulfate, filtered, and concentrated in vacuo. The resulting crudeproduct was purified by silica gel chromatography to give 4-iodooxepane.

STEP 4. 2-FLUORO-3-(OXEPAN-4-YL)PYRAZINE

A mixture of chlorotrimethylsilane (0.11 mL, 0.87 mmol) and 1,2dibromoethane (0.075 mL, 0.87 mmol) was added slowly to a stirredmixture of zinc dust (0.71 g, 10.9 mmol) in DMA (2 mL) at roomtemperature under a nitrogen atmosphere. The mixture was stirred for 15min before a solution of 4-iodooxepane (1.97 g, 8.71 mmol) in DMA (5 mL)was added dropwise via syringe. The reaction mixture was stirred at roomtemperature for an additional 30 min before being warmed to 60° C. for15 min. The reaction mixture was cooled to room temperature and addeddirectly via syringe to a stirred mixture of 2-fluoro-3-iodopyrazine(1.39 g, 6.23 mmol), copper(i) iodide (0.12 g, 0.62 mmol), anddichloro(1,1-bis(diphenylphosphinoferrocene))palladium(ii) (0.25 g, 0.31mmol) in DMA (8 mL) under an argon atmosphere. The reaction mixture wasstirred at 80° C. for 3 h. The reaction mixture was cooled to roomtemperature, quenched with sat. ammonium chloride, and extracted withEtOAc. The organic layer was separated, washed with sat. sodiumchloride, dried over magnesium sulfate, filtered, and concentrated invacuo. The resulting crude product was purified by silica gelchromatography to give 2-fluoro-3-(oxepan-4-yl)pyrazine. [M+1]=197.1.

STEP 5.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(OXEPAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

2-Fluoro-3-(oxepan-4-yl)pyrazine (0.08 g, 0.40 mmol),(1H-benzo[c]imidazol-2-yl)(4-hydroxyphenyl)methanone (028 g, 1.19 mmol),and cesium carbonate (0.39 mL, 1.19 mmol) were mixed in NMP (1 mL) undera nitrogen atmosphere. The reaction mixture was stirred at 140° C. for 6h. The reaction mixture was cooled to room temperature, diluted withwater, and extracted with EtOAc (2×). The combined organic layers werewashed with 1 M aqueous sodium hydroxide, washed with sat. sodiumchloride, dried over magnesium sulfate, and concentrated in vacuo. Theresulting crude product was purified by silica gel chromatography togive(1H-benzo[c]imidazol-2-yl)(4-(3-(oxepan-4-yl)pyrazin-2-yloxy)phenyl)methanone.MS (ESI, pos. ion) m/z: 415.1 (M+1). IC50 (uM) +++++.

Example 199(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(4,4-DIFLUOROCYCLOHEX-1-ENYL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1. 4,4-DIFLUOROCYCLOHEX-1-ENYL TRIFLUOROMETHANESULFONATE

To a round bottomed flask was added diisopropylamine (3.76 mL, 26.8mmol) in THF. The temperature was brought to −78° C. and n-butyllithium(10.74 mL, 26.8 mmol) (2.5M in hexanes) was added dropwise. Thetemperature was brought to 0° C. and was allowed to stir for 10 minutes.The temperature was brought back to −78° C. and4,4-difluorocyclohexanone (3.0000 g, 22.37 mmol) was added and allowedto stir. After 30 minutes, triflate anhydride (5.63 mL, 33.6 mmol) wasadded and the temperature was allowed to slowly warm to roomtemperature. The reaction mixture was diluted with 50% sodium chloridesolution and extracted with DCM. The organic extract was washed withwater, brine, dried with magnesium sulfate, filtered, and concentratedto provide 4,4-difluorocyclohex-1-enyl trifluoromethanesulfonate.

STEP 2.2-(4,4-DIFLUOROCYCLOHEX-1-ENYL)-4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLANE

To a sealed tube was added 4,4-difluorocyclohex-1-enyltrifluoromethanesulfonate (5.950 g, 22.35 mmol), bis(pinacolato)diboron(6.81 g, 26.8 mmol), potassium acetate (3.77 mL, 60.4 mmol), and dppf(0.867 g, 1.565 mmol) in dioxane (75 mL) to stir at 130° C. overnight.Reaction was worked up via seperatory funnel. The crude product wasadsorbed onto a plug of silica gel and chromatographed through aRedi-Sep® pre-packed silica gel column (40 g), eluting with isocraticDCM, to provide2-(4,4-difluorocyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

STEP 3.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(4,4-DIFLUOROCYCLOHEX-1-ENYL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

To a round bottomed flask was added(1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone(0.5018 g, 1.431 mmol),2-(4,4-difluorocyclohex-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.698 g, 2.86 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.080 g, 0.114 mmol), and sodium carbonate (0.455 g, 4.29 mmol) inDME (3.58 mL) and water (1.192 mL) at 80° C. to stir overnight. Uponcompletion, solvent was removed. The crude product was purified byreverse-phase preparative HPLC using a Phenomenex Synergi column, 4micron, MAX-RP, 80 Å, 150×30 MM, 0.1% TFA in CH₃CN/H₂O, gradient 10% to100% over 15 min to provide(1H-benzo[d]imidazol-2-yl)(4-(3-(4,4-difluorocyclohex-1-enyl)pyrazin-2-yloxy)phenyl)methanone.MS (ESI, pos. ion) m/z: 433.0 (M+1). IC50 (uM) +++++.

Example 2004-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)TETRAHYDRO-2H-PYRAN-4-CARBONITRILE

STEP 1: 4-(3-CHLOROPYRAZIN-2-YL)TETRAHYDRO-2H-PYRAN-4-CARBONITRILE

To a solution of 2,3-dichloropyrazine (1.219 g, 8.18 mmol) andtetrahydro-2H-pyran-4-carbonitrile (1 g, 9.00 mmol) in Toluene (16.36mL) at room temperature was added LiHMDS (18.00 mL, 18.00 mmol)dropwise. The reaction mixture was stirred overnight at roomtemperature. Reaction was quenched with saturated NH₄Cl and extractedwith EtOAc. Two purifications with Biotage (0-10% MeOH/DCM & 0-100%EtOAc/Hexane) were conducted to isolate product.

STEP 2:4-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)TETRAHYDRO-2H-PYRAN-4-CARBONITRILE

To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (0.097 g, 0.402mmol) and 4-(3-chloropyrazin-2-yl)tetrahydro-2H-pyran-4-carbonitrile(0.09 g, 0.402 mmol) in DMSO (1 mL) was added cesium carbonate (0.262 g,0.805 mmol). The resulting mixture was heated to 60° C. overnight.Purification by Biotage (0-100% EtOAc/hexane) provided product. MS (ESI,pos. ion) m/z: 430.0 (M+1). IC50 (uM) +++++.

Example 201N-METHYL-N-(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

STEP 1: METHYL 4-(3-CHLOROPYRAZIN-2-YL)TETRAHYDRO-2H-PYRAN-4-CARBOXYLATE

To a solution of 2,3-dichloropyrazine (1.45 g, 9.73 mmol) and methyltetrahydro-2H-pyran-4-carboxylate (2.60 mL, 19.47 mmol) in Toluene(19.47 mL) at room temperature was added LiHMDS (19.47 mL, 19.47 mmol,1M solution) dropwise. After overnight room temperature stirring,reaction was quenched with saturated NH₄Cl solution and extracted withEtOAc. Purification by Biotage (0-10% MeOH/DCM) produced product.

STEP 2:N-METHYL-N-(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (0.094 g, 0.390mmol) and methyl4-(3-chloropyrazin-2-yl)tetrahydro-2H-pyran-4-carboxylate (0.1 g, 0.390mmol) in DMSO (1 mL) was added cesium carbonate (0.254 g, 0.779 mmol).The resulting mixture was heated to 163° C. for ˜20 minutes. Reactionmixture was cooled back to 100 C and stirred overnight. Aqueous work upwith multiple water and brine washes to remove DMSO and extraction withDCM. Purification by Shimadzu (phenomenex Gemini C18 5 um 100×30 mm; 254UV; solvent A=0.1% TFA in water, solvent B=0.1% TFA in ACN; gradientrun: 35% B to 80% B in 9 min; 1 min@ 80% B; flow rate=30 ml/min; 2 peakscontained mass 418: R1 =3.91 to 4.26 min; R2=5.83 to 6.36 min) to affordthe product. MS (ESI, pos. ion) m/z: 419.0 (M+1). IC50 (uM) +++++.

Example 2024-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)TETRAHYDRO-2H-PYRAN-4-OL

STEP 1: 4-(3-FLUOROPYRAZIN-2-YL)TETRAHYDRO-2H-PYRAN-4-OL

A 2.5M solution of nbuli (4.49 mL, 11.22 mmol)/hexane in THF (3 mL) wasfirst cooled to −78° C. To the cooled solution was added dropwise,2,2,6,6-tetramethylpiperidine (2.065 mL, 12.24 mmol). The dry ice bathwas then switched to a 0° C. bath. The reaction mixture was stirred for10 min at 0° C. and then the dry ice bath was switched back to recoolthe reaction mixture to −78° C. To the cooled solution was added2-fluoropyrazine (1 g, 10.20 mmol), dropwise. After 5 min of stirring at−78° C., a solution of dihydro-2H-pyran-4(3H)-one (0.937 mL, 10.20 mmol)in 0.6 mL of THF was added dropwise. The resulting mixture was allowedto gradually warm to room temperature overnight. Reaction was quenchedwith saturated NH₄Cl and extracted with EtOAc. Purification by Biotage(0-100% EtOAc/hexane) produced product.

STEP 2:4-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)TETRAHYDRO-2H-PYRAN-4-OL

To a solution of 4-(3-fluoropyrazin-2-yl)tetrahydro-2H-pyran-4-ol (0.1g, 0.505 mmol) in DMSO (1 mL) was added4-(benzo[d]thiazol-2-ylamino)phenol (0.183 g, 0.757 mmol) and cesiumcarbonate (0.329 g, 1.009 mmol). The resulting mixture was heated to 80°C. overnight. Reaction mixture was diluted with DCM and washed withalternating washes of water and brine to remove DMSO. Purification byBiotage (0-10% MeOH/DCM) produced product. MS (ESI, pos. ion) m/z: 421.1(M+1). IC50 (uM) +++++.

Example 203(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(4-FLUOROTETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1: 4-(3-FLUOROPYRAZIN-2-YL)TETRAHYDRO-2H-PYRAN-4-OL

To a solution of 2-fluoro-3-iodopyrazine (1 g, 4.46 mmol) in THF (4.46mL) at 0° C. was added isopropylmagnesium chloride lithium chloridecomplex, 1.0M solution in THF (4.87 mL, 4.46 mmol). The resultingmixture was stirred for 5 min before addition ofdihydro-2H-pyran-4(3H)-one (0.410 mL, 4.46 mmol). Reaction mixture wasallowed to warm to room temperature and stirred overnight. Purificationby Biotage (0-100% EtOAc/hexane) produced the product.

STEP 2: 2-FLUORO-3-(4-FLUOROTETRAHYDRO-2H-PYRAN-4-YL)PYRAZINE

A solution of 4-(3-fluoropyrazin-2-yl)tetrahydro-2H-pyran-4-ol (0.4 g,2.018 mmol) in CH₂Cl₂ (6.73 mL) was cooled to 0° C. DAST (0.533 mL, 4.04mmol) was added to the reaction mixture dropwise and the resultingmixture was allowed to stir at 0° C. for 2 hr. A solution of saturatedsodium carbonate was added dropwise to the reaction mixture at 0° C. toquench the reaction. The heterogeneous mixture was stirred vigorouslyfor 1 hr to ensure complete quenching. Mixture was transferred to aseparatory funnel and the layers were separated after addition of moreDCM and saturated bicarbonate solution. The organic layer was dried overmagnesium sulfate and rotovapped to remove the volatile solvent.

STEP 3:(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(4-FLUOROTETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

A solution of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone(0.543 g, 2.278mmol),2-fluoro-3-(4-fluorotetrahydro-2H-pyran-4-yl)pyrazine (0.304 g,1.519 mmol), cesium carbonate (0.990 g, 3.04 mmol), andN-Methyl-2-pyrrolidinone (3.04 mL) in a sealed tube was heated to 100°C. overnight. Aqueous work up with DCM and washing with alternatingwater and brine washes. The organic layer was rotovapped and loaded ontoa Biotage samplet. Purification by Biotage (0-100% EtOAc/hexane, slowgradient, over 12 CV). The product containing fractions wereconcentrated by rotovap. The residue was further purified by triturationwith EtOH at room temperature overnight to produce product. MS (ESI,pos. ion) m/z: 419.1 (M+1). IC50 (uM) +++++.

Example 204N-(4-(3-(4-FLUOROTETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

STEP 1: 4-(3-FLUOROPYRAZIN-2-YL)TETRAHYDRO-2H-PYRAN-4-OL

A 2.5M solution of nBuLi (4.49 mL, 11.22 mmol)/hexane in THF (3 mL) wasfirst cooled to −78° C. To the cooled solution was added dropwise,2,2,6,6-tetramethylpiperidine (2.065 mL, 12.24 mmol). The dry ice bathwas then switched to a 0° C. bath. The reaction mixture was stirred for10 min at 0° C. and then the dry ice bath was switched back to recoolthe reaction mixture to −78° C. To the cooled solution was added2-fluoropyrazine (1 g, 10.20 mmol), dropwise. After 5 min of stirring at−78° C., a solution of dihydro-2H-pyran-4(3H)-one (0.937 mL, 10.20 mmol)in 0.6 mL of THF was added dropwise. The resulting mixture was allowedto gradually warm to room temperature overnight. Reaction was quenchedwith saturated NH₄Cl and extracted with EtOAc. Purification by Biotage(0-100% EtOAc/hexane) produced product.

STEP 2: 2-FLUORO-3-(4-FLUOROTETRAHYDRO-2H-PYRAN-4-YL)PYRAZINE

To a solution of 4-(3-fluoropyrazin-2-yl)tetrahydro-2H-pyran-4-ol (0.123g, 0.621 mmol) in DCM (2 mL) cooled to 0° C. was added dropwise dast(0.164 mL, 1.241 mmol). The resulting mixture was stirred for 2 hr.Reaction was quenched with dropwise addition of saturated NaHCO₃solution and back extracted with DCM to produce product.

STEP 3:N-(4-(3-(4-FLUOROTETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

To a solution of 2-fluoro-3-(4-fluorotetrahydro-2H-pyran-4-yl)pyrazine(0.055 g, 0.275 mmol) and 4-(benzo[d]thiazol-2-ylamino)phenol (0.100 g,0.412 mmol) in DMSO (0.9 mL) was added cesium carbonate (0.179 g, 0.549mmol). The resulting mixture was heated to 80° C. overnight. Thereaction mixture was partitioned between water, brine and DCM. Theaqueous layer was back extracted with DCM and the combined organic layerwas dried (Na₂SO₄) and concentrated. Purification by prep-plate TLC (5%MeOH/DCM) produced product. MS (ESI, pos. ion) m/z: 423.0 (M+1). IC50(uM) +++++.

Example 205 1-TERT-BUTYL 4-METHYL4-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)PIPERIDINE-1,4-DICARBOXYLATE

STEP 1. 1-TERT-BUTYL 4-METHYL PIPERIDINE-1,4-DICARBOXYLATE

To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid(10.50 g, 45.8 mmol) in DMF (200 mL) was added potassium carbonate (6.33g, 45.8 mmol) followed by iodomethane (3.42 mL, 55.0 mmol). The reactionwas stirred under N₂ at RT 3 h. The reaction was poured into 10% aqueousK₂CO₃ (500 mL) and extracted with EtOAc (3×150 mL). The combined organiclayers were washed with saturated NaCl (2×150 mL), dried (MgSO₄) andconcentrated to give 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate(11.8 g, 48.5 mmol, 106% yield) as a light yellow oil.

STEP 2. 1-TERT-BUTYL 4-METHYL4-(3-CHLOROPYRAZIN-2-YL)PIPERIDINE-1,4-DICARBOXYLATE

To a vial containing 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate(408 mg, 1.678 mmol) and 2,3-dichloropyrazine (250 mg, 1.678 mmol) inTHF (2.5 mL) at rt under N₂ is added dropwise LiHMDS (1.678 mL, 1.678mmol). The reaction was stirred at rt 16 h. The reaction mixture waspoured into H₂O (10 mL) and extracted with EtOAc (3×20 mL). The combinedorganic layers were washed with saturated NaCl (10 mL), dried (MgSO₄),and concentrated. Purification by ISCO (40 g SiO₂, 0-75% EtOAc/Hexane)gives 1-tert-butyl 4-methyl4-(3-chloropyrazin-2-yl)piperidine-1,4-dicarboxylate (565 mg, 1.588mmol, 95% yield) as a clear, colorless oil. [M+Na]=378.0

STEP 3. 1-TERT-BUTYL 4-METHYL4-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)PIPERIDINE-1,4-DICARBOXYLATE

To a vial with 1-tert-butyl 4-methyl4-(3-chloropyrazin-2-yl)piperidine-1,4-dicarboxylate (58 mg, 0.163mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (39.5 mg, 0.163 mmol), andcesium carbonate (106 mg, 0.326 mmol) under N₂ is added DMSO (1.0 mL).The reaction is heated to 100° C. in an oil bath 3 h. The reaction wascooled to rt, added to H₂O (5 mL) and extracted with EtOAc (3×5 mL). Thecombined organic layers were dried (MgSO₄) and concentrated. The residuewas purified by RPHPLC to give 1-tert-butyl 4-methyl4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1,4-dicarboxylate(36 mg, 0.064 mmol, 39.3% yield) as a white solid. [M+1]=562.1. IC50(uM) +++++.

Example 206 TERT-BUTYL4-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)-4-(HYDROXYMETHYL)PIPERIDINE-1-CARBOXYLATE

STEP 1. 1-TERT-BUTYL 4-METHYL4-(3-(4-(BENZO[D]THIAZOL-2-YL(TERT-BUTOXYCARBONYL)AMINO)PHENOXY)PYRAZIN-2-YL)PIPERIDINE-1,4-DICARBOXYLATE

To a solution of 1-tert-butyl 4-methyl4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1,4-dicarboxylate(266 mg, 0.474 mmol) in DCM (10 mL) was added (Boc)₂O, 1M in THF (0.5mL, 0.500 mmol). After 24 hours, the crude reaction was adsorbed onto aplug of silica gel and chromatographed through a Redi-Sep® pre-packedsilica gel column (12 g), eluting with 0% to 50% EtOAc in hexane, toprovide 1-tert-butyl 4-methyl4-(3-(4-(benzo[d]thiazol-2-yl(tert-butoxycarbonyl)amino)phenoxy)pyrazin-2-yl)piperidine-1,4-dicarboxylate(122 mg, 0.184 mmol) as a colorless oil.

STEP 2. TERT-BUTYL4-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)-4-(HYDROXYMETHYL)PIPERIDINE-1-CARBOXYLATE

To an ice cooled solution of 1-tert-butyl 4-methyl4-(3-(4-(benzo[d]thiazol-2-yl(tert-butoxycarbonyl)amino)phenoxy)pyrazin-2-yl)piperidine-1,4-dicarboxylate(122 mg, 0.184 mmol) in dry THF (5 mL) was added LAH, 2M in THF (0.08mL, 0.160 mmol). After stirring for 16 hours, LC-MS indicates a mixtureof product, starting material, desBoc starting material and desBocproduct. The reaction was treated with more LAH, 2M in THF (0.09 mL).After 4 hours, LC-MS shows one main peak that is consistent with desiredproduct minus Boc (m/z 534 MH+). The reaction was quenched with sat'drochelle's salt and diluted with EtOAc (10 mL). The aqeuous layer wasextracted with EtOAc (10 mL) and the combined EtOAc layers wereconcentrated in vacuo. The brown residue was purified by reverse-phasepreparative HPLC (Shimadzu) on a Phenomenex Gemini column (5 micron,C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with an lineargradient of 10% to 80% MeCN (0.1% TFA) in water (0.1% TFA) over 20minutes to give tert-butyl4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-4-(hydroxymethyl)piperidine-1-carboxylate(8.2 mg) as a TFA salt and white solid after lypholization. MS (ESI,pos. ion) m/z: 534.0 (M+1). IC50 (uM) ++++.

Example 207N-(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)-1H-BENZO[D]IMIDAZOL-2-AMINE

STEP 1. (TETRAHYDRO-2H-PYRAN-4-YL)MAGNESIUM BROMIDE

To a solution of Reike's magnesium in THF at 0° C. was added4-bromotetrahydro-2H-pyran (1.000 g, 6.06 mmol) to stir for 1 hr toprovide (tetrahydro-2H-pyran-4-yl)magnesium bromide.

STEP 2. 4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)ANILINE

To a round bottomed flask was added 4-(3-chloropyrazin-2-yloxy)aniline(1.2276 g, 5.54 mmol) dissolved in a mixture of THF (8.86 mL) and NMP(2.215 mL). Iron(iii) acetylacetonate (0.098 g, 0.277 mmol) was addedand the temperature was brought to 0° C.(Tetrahydro-2H-pyran-4-yl)magnesium chloride (8.31 mL, 6.65 mmol) wasadded dropwise to the reaction mixture. Upon completion, the reactionwas quenched with saturated ammonia chloride solution. The reactionmixture was diluted with water and extracted with EtOAc. The organicextract was washed with water, brine, dried with magnesium sulfate,filtered, and concentrated. The crude product was adsorbed onto a plugof silica gel and chromatographed through a Redi-Sep® pre-packed silicagel column (120 g), eluting with a gradient of 10% to 100% EtOAc inhexane, to provide4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline.

STEP 3.N-(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)-1H-BENZO[D]IMIDAZOL-2-AMINE

A glass microwave reaction vessel was charged with4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline (0.1536 g, 0.566mmol) and 2-chlorobenzimidazole (0.095 g, 0.623 mmol) in IPA. Thereaction mixture was stirred and heated in a Biotage Initiator microwavereactor at 170° C. for 30 min. The crude product was adsorbed onto aplug of silica gel and chromatographed through a Biotage pre-packedsilica gel column (40S), eluting with a gradient of 1% to 5% MeOH inDCM, to provideN-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine.MS (ESI, pos. ion) m/z: 388.0 (M+1). IC50 (uM) +++++.

Example 208N-(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

STEP 1. (TETRAHYDRO-2H-PYRAN-4-YL)MAGNESIUM BROMIDE

To a solution of Reike's magnesium in THF at 0° C. was added4-bromotetrahydro-2H-pyran (1.000 g, 6.06 mmol) to stir for 1 hr toprovide (tetrahydro-2H-pyran-4-yl)magnesium bromide.

STEP 2.N-(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

To a round bottomed flask was addedN-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.3000 g,0.846 mmol) dissolved in a mixture of THF (1.353 mL) and NMP (0.338 mL).Iron(III)acetylacetonate (0.015 g, 0.042 mmol) was added and thetemperature was brought to 0° C. (Tetrahydro-2H-pyran-4-yl)magnesiumbromide (3.70 mL, 2.96 mmol) was added dropwise to the reaction. Thereaction was quenched with sat. ammonium chloride. The reaction mixturewas diluted with water and extracted with EtOAc. The organic extract waswashed with water, brine, dried with magnesium sulfate, filtered, andconcentrated. LC showed formation ofN-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amineand N-(4-(pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. The crudeproduct was adsorbed onto a plug of silica gel and chromatographedthrough a Biotage pre-packed silica gel column (40S), eluting with agradient of 1% to 5% MeOH in DCM, to provideN-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine.MS (ESI, pos. ion) m/z: 405.0 (M+1). IC50 (uM) +++++.

Example 2097-METHOXY-N-(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)-1H-BENZO[D]IMIDAZOL-2-AMINE

STEP 1. 2-(3,6-DIHYDRO-2H-PYRAN-4-YL)-3-FLUOROPYRAZINE

To a glass microwave vial was added 2-fluoro-3-iodopyrazine (1.6485 g,7.36 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.319 g, 11.04 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.413 g, 0.589 mmol), and sodium carbonate (3.90 g, 36.8 mmol) inDME (19.63 mL) and water (4.91 mL) to stir at 80° C. overnight. Reactionwas allowed to cool to room temperature. The reaction mixture wasdiluted with water and extracted with DCM. The organic extract waswashed with water, brine, dried with magnesium sulfate, filtered, andconcentrated. The crude product was adsorbed onto a plug of silica geland chromatographed through a Biotage pre-packed silica gel column(40S), eluting with a gradient of 10% to 100% EtOAc in hexane, toprovide 2-(3,6-dihydro-2H-pyran-4-yl)-3-fluoropyrazine. [M+H]=181.1.

STEP 2. 2-FLUORO-3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZINE

To a round bottomed flask was added2-(3,6-dihydro-2H-pyran-4-yl)-3-fluoropyrazine (1.1754 g, 6.52 mmol) andpalladium hydroxide on carbon (0.458 g, 0.652 mmol) in EtOAc (21.75 mL).The round bottomed flask was flushed with argon and then placed undervacuum three times. A hydrogen balloon was then attached to thereaction. After stirring overnight, the reaction was filtered throughcelite to provide 2-fluoro-3-(Tetrahydro-2H-pyran-4-yl)pyrazine.[M+H]=183.1.

STEP 3. 4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)ANILINE

To a round bottomed flask was added2-fluoro-3-(tetrahydro-2H-pyran-4-yl)pyrazine (1.1147 g, 6.12 mmol),4-aminophenol (0.801 g, 7.34 mmol), and cesium carbonate (5.98 g, 18.35mmol) in DMSO (20.39 mL) in DMSO at 110° C. to stir overnight. Thereaction was allowed to cool to room temperature. The reaction mixturewas diluted with water and extracted with DCM. The organic extract waswashed with 50% sodium chloride solution, dried with magnesium sulfate,filtered, and concentrated. The crude product was adsorbed onto a plugof silica gel and chromatographed through a Biotage pre-packed silicagel column (40M), eluting with a gradient of 1% to 5% MeOH in DCM, toprovide 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline.[M+H]=272.1.

STEP 4. 4-METHOXY-1H-BENZO[D]IMIDAZOL-2(3H)-ONE

To a round bottomed flask was added 2-amino-3-methoxybenzoic acid(2.2705 g, 13.58 mmol), diphenyl phosphorazidate (3.51 mL, 16.30 mmol),and triethylamine (3.79 mL, 27.2 mmol) in THF to stir at 80° C. Uponcompletion the reaction was allowed to cool to room temperature. Solventwas evaporated. The residue was taken up in DCM. The reaction mixturewas diluted with water and extracted with DCM. A white precipitate wasnoted to form during extraction The solid was filtered to provide4-methoxy-1H-benzo[d]imidazol-2(3H)-one. [M+H]=165.0.

STEP 5. 2-CHLORO-7-METHOXY-1H-BENZO[D]IMIDAZOLE

To a round bottomed flask was added4-methoxy-1H-benzo[d]imidazol-2(3H)-one (1.8163 g, 11.06 mmol). POCl₃(1.031 mL, 11.06 mmol) was added and the reaction was brought to reflux.Upon completion, POCL₃ was evaporated off. The residue was taken up inDCM. The reaction mixture was diluted with water and saturated sodiumbicarbonate and extracted with DCM. The organic extract was washed withsat. sodium bicarbonate solution, water, brine, dried with, magnesiumsulfate, filtered, and concentrated to provide2-Chloro-7-methoxy-1H-benzo[d]imidazole. [M+H]=182.9.

STEP 6.7-METHOXY-N-(4-(3-(TETRAHYDRO-2H-PYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)-1H-BENZO[D]IMIDAZOL-2-AMINE

A glass microwave reaction vessel was charged with4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline (0.2573 g, 0.952mmol) and 2-chloro-1-(4-methoxybenzyl)-1H-benzo[d]imidazole (0.312 g,1.142 mmol) in IPA. The reaction mixture was stirred and heated in aBiotage Initiator microwave reactor at 170° C. for 30 min. The crudeproduct was adsorbed onto a plug of silica gel and chromatographedthrough a Biotage pre-packed silica gel column (40S), eluting with agradient of 10% to 80% EtOAc in hexane, to provide1-(4-methoxybenzyl)-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine.MS (ESI, pos. ion) m/z: 507.1 (M+1). IC50 (uM) +++++.

TABLE (VIIIA) EXAMPLES 210 TO 219 ARE TABULATED BELOW: Ex IC50 MS #Structure (uM) IUPAC names (M + 1) 210

+++++ (rac)-3-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)cyclo- hexanone 413 211

+++++ 4-(3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)pyrazin-2-yl)tetrahydro- 2H-pyran-4- carbonitrile 426 212

+++++ methyl 4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2-yl)tetrahydro- 2H-pyran-4-carboxylate 463 213

+++++ (1H-benzo[d]imidazol- 2-yl)(4-(3-(4- hydroxytetrahydro-2H-pyran-4-yl)pyrazin-2- yloxy)phenyl)methanone 417 214

+++++ 6-fluoro-N-(4-(3- (tetrahydro-2H-pyran-4- yl)pyrazin-2-yloxy)phenyl)benzo[d] thiazol-2-amine 423 215

+++++ N-(2-fluoro-4-(3- (tetrahydro-2H-pyran-4- yl)pyrazin-2-yloxy)phenyl)benzo[d] thiazol-2-amine 423 216

+ N-(2-fluoro-4-(pyrazin- 2- yloxy)phenyl)benzo[d] thiazol-2-amine 339217

+ 7-fluoro-N-(4-(pyrazin- 2- yloxy)phenyl)benzo[d] thiazol-2-amine 339218

+++++ 5-fluoro-N-(4-(3- (tetrahydro-2H-pyran-4- yl)pyrazin-2-yloxy)phenyl)benzo[d] thiazol-2-amine 423 219

+ 5-fluoro-N-(4-(pyrazin- 2- yloxy)phenyl)benzo[d] thiazol-2-amine 339

TABLE (VIIIB) PREPARATION OF EXAMPLES 210 TO 219 ARE TABULATED BELOW:How Different Synthetic from Main Ex # Scheme Route Reagent Difference210 18 Reaction performed at 140° C.

211 23 lower heating temperature to 60° C.

212 24 lower heating Same temperature to 60° C. 213 25 Same

214 30 Same

215 30 Same

216 30 Same

217 30 Same

218 30 Same

219 30 Same

Example 220(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-CYCLOPENTYLPYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1. 2-CHLORO-3-CYCLOPENTYLPYRAZINE

To a suspension of zinc dust (2.00 g, 30.6 mmol) inN,N-dimethylacetamide (20 mL) was added a mixture of trimethylsilylchloride and 1,2-dibromoethane (7:5, v/v, 0.95 mL total volume) dropwiseover 5 minutes. The mixture was stirred for 15 min before cyclopentyliodide (5.00 g, 25.5 mmol) was added dropwise over 15 min. This mixturewas stirred for an additional 15 min and then was added via syringe over5 min to a mixture of copper(I) iodide (0.30 g, 1.60 mmol),dichloro(1,1-bis(diphenylphosphinoferrocene))palladium(II) (0.65 g, 0.80mmol), and 2,3-dichloropyrazine (1.66 mL, 16.0 mmol) inN,N-dimethylacetamide (30 mL) under argon atmosphere. The mixture washeated to 80° C. for 7 h, cooled to room temperature and partitionedbetween ethyl acetate and saturated aqueous ammonium chloride. Theresulting layers were separated and the aqueous layer was extracted withethyl acetate (1×). The combined extracts were washed with water (2×),saturated aqueous sodium chloride (1×), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedby silica gel chromatography to give 2-chloro-3-cyclopentylpyrazine.

STEP 2.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-CYCLOPENTYLPYRAZIN-2-YLOXY)PHENYL)METHANONE

A mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.98g, 4.11 mmol), cesium carbonate (1.34 g, 4.11 mmol), and2-chloro-3-cyclopentylpyrazine (0.38 g, 2.05 mmol) in1-methyl-2-pyrrolidinone (2 mL) under argon was heated to 140° C. for 24h. The mixture was cooled to room temperature and then partitionedbetween ethyl acetate and water. The resulting layers were separated andthe organic layer was washed with 1N aqueous sodium hydroxide (2×),saturated aqueous sodium chloride (1×), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. The resulting oil waspurified by silica gel chromatography to give(1H-benzo[d]imidazol-2-yl)(4-(3-cyclopentylpyrazin-2-yloxy)phenyl)methanone.MS (ESI, pos. ion) m/z: 385.2 (M+1). IC50 (uM) ++++.

Example 221N-(4-(3-(TETRAHYDROFURAN-3-YL)PYRAZIN-2-YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE

A mixture ofN-(4-(3-chloropyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine (0.600 g,1.691 mmol), 2,5-dihydrofuran (1.25 mL, 16.53 mmol, Aldrich),bis(tri-tert-butylphosphine)palladium (0) (0.092 g, 0.180 mmol, Strem)and N-methyldicyclohexylamine (0.700 mL, 3.30 mmol, Aldrich) in DMF (5mL) was sealed under argon in a 20 mL microwave reaction vessel andheated at 80° C. thermally overnight. The solvent was removed in vacuoand the residue was dissolved in dioxane. To the solution was added 10%palladium on carbon, wet (0.178 g, 0.167 mmol) and the mixture wasevacuated and purged with hydrogen (1 atm) and the reaction was stirredat rt. Upon complete conversion the mixture was diluted with MeOH,evaporated onto silica gel and purified by flash chromatography (Isco,(80 gram)) eluting with 2M NH₃ in MeOH:CH₂Cl₂ (0:1→3:97) to give impurematerial. The fractions containing product were concentrated andpurified by reverse-phase HPLC (Gilson; Gemini-NX 10μ C18 110A AXIA,100×50 mm column) eluting with 0.1% TFA-H₂O:0.1% TFA CH₃CN (9:1→1:9).The fractions containing the desired product were combined andconcentrated in vacuo to give a solid. The residue was dissolved in MeOHand loaded onto an SCX II cartridge eluting with MeOH then 2M NH₃ inMeOH to give a yellow crystalline solid. MS (ESI, pos. ion) m/z: 391.0(M+1). IC50 (uM) +++++.

Example 2221H-BENZO[D]IMIDAZOLE-2-YL(4-(3-(TETRAHYDRO-2H-THIOPYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1: 3,6-DIHYDRO-2H-THIOPYRAN-4-YL-TRIFLUOROMETHANESULFONATE

To a stirred solution of dihydro-2H-thiopyran-4(3H)-one (5.0 g, 43.0mmol) in THF (30 mL) at −78° C. was added LDA (25.8 mL, 51.6 mmol)dropwise. After stirring for 1 h, a solution of2-(m,n-bis(trifluoromethylsulfonyl)amino)-5-chloropyridine (17.74 g,45.2 mmol) in THF (50 mL) was added. The reaction mixture was thenwarmed to RT and stirred overnight, quenched by saturated NH₄Cl,extracted with ether (3×), dried over MgSO₄, concentrated and purifiedby ISCO (0-10% EtOAc/Hexanes) to give the yellow oil. MS [M+1]: 249.2.

STEP 2:2-(3,6-DIHYDRO-2H-THIOPYRAN-4-YL)-4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLANE

A mixture of 3,6-dihydro-2H-thiopyran-4-yltrifluoromethanesulfonate (4.5g, 18.13 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.90 g,27.2 mmol), potassium acetate (5.34 g, 54.4 mmol), and PdCl₂(dppf)₂(1.480 g, 1.813 mmol) in p-dioxane/H₂O (10:1, 22 ml) was heated at 100°C. in 24 h, cooled, diluted with EtOAc, washed with H₂O, dried overMgSO₄, concentrated and purified by ISCO (0-10% EtOAc/Hexanes) to givethe yellow oil. MS [M+1]: 227.1.

STEP 3: 4-HYDROXY-N-METHOXY-N-METHYLBENZAMIDE

A mixture of 4-hydroxybenzoic acid (20.29 g, 147 mmol), N,O-dimethylhydroxylamine hydrochloride (21.49 g, 220 mmol),N-ethyl-N-isopropylpropan-2-amine (77 mL, 441 mmol), hobt (22.50 g, 147mmol), and EDC (33.8 g, 176 mmol) in DMF (100 mL) was stirred at RT in24 h. H₂O was added, extracted with ether (3×), dried over MgSO₄,concentrated, and purified by ISCO (40% EtOAc/Hexanes) to give thetitled compound. MS [M+1]: 182.1.

STEP 4: 4-(3-CHLOROPYRAZIN-2-YLOXY)-N-METHOXY-N-METHYLBENZAMIDE

A mixture of 4-hydroxy-N-methoxy-N-methylbenzamide (6.50 g, 35.9 mmol),2,3-dichloropyrazine (6.95 g, 46.6 mmol), and potassium carbonate (12.40g, 90 mmol) in acetonitrile (70 mL) was heated at reflux in 18 h. Thereaction mixture was cooled, concentrated, taken up in H₂O, extractedwith EtOAc, dried over MgSO₄, concentrated and purified by ISCO (50%EtOAc/Hexanes) to give the titled compound. MS [M+1]: 294.1.

STEP 5:4-(3-(3,6-DIHYDRO-2H-THIOPYRAN-4-YL)PYRAZIN-2-YLOXY)-N-METHOXY-N-METHYLBENZAMIDE

A mixture of 4-(3-chloropyrazin-2-yloxy)-N-methoxy-N-methylbenzamide(1.4 g, 4.77 mmol),2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.132 g, 5.01 mmol), potassium carbonate (1.976 g, 14.30 mmol), andbis(tri-tert-butylphosphine)palladium(0) (0.244 g, 0.477 mmol) inp-dioxane/H₂O (10:1, 11 ml) was heated to 120° C. in 4 h, cooled, takenup in H₂O, extracted with EtOAc (3×), dried over MgSO₄, concentrated andpurified by ISCO (50% EtOAc/hexanes) to give the titled compound. MS[M+1]: 358.1.

STEP 6:N-METHOXY-N-METHYL-4-(3-(TETRAHYDRO-2H-THIOPYRAN-4-YL)PYRAZIN-2-YLOXY)BENZAMIDE

A solution of4-(3-(3,6-dihydro-2H-thiopyran-4-yl)pyrazin-2-yloxy)-N-methoxy-N-methylbenzamide(0.500 g, 1.399 mmol) in MeOH (10 ml) was hydrogenated at RT in 10% Pd/C(0.200 mg) in 72 h. The solid was filtered off, and the filtrate wasconcentrated and purified by ISCO (3% MeOH/DCM) to give the titlecompound. MS [M+1]: 360.1.

STEP 7:1H-BENZO[D]IMIDAZOLE-2-YL(4-(3-(TETRAHYDRO-2H-THIOPYRAN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

A mixture of 1H-benzo[d]imidazole (0.039 g, 0.334 mmol),triisopropoxymethane (0.529 g, 2.78 mmol), benzenesulfonic acid (2.200mg, 0.014 mmol) in toluene (5 mL) was heated at reflux for 3 h. Themixture was cooled, neutralized with diisopropylamine (0.1 ml),concentrated to dryness and diluted with 1 ml THF. The above solutionwas added to a stirred mixture ofN-methoxy-N-methyl-4-(3-(tetrahydro-2H-thiopyran-4-yl)pyrazin-2-yloxy)benzamide(0.100 g, 0.278 mmol) in THF (3 mL). The resulting mixture was cooled to0° C. and LDA (0.167 mL, 0.334 mmol) was added dropwise. The reactionmixture was stirred at RT overnight, quenched with saturated NH₄Cl,extracted with EtOAc (3×), dried over MgSO4, concentrated and purifiedby ISCO (0-5% MeOH/DCM) to give the title compound as a white solid. MS(ESI, pos. ion) m/z: 416.1 (M+1). IC50 (uM) +++++.

TABLE (IXA) EXAMPLE 223 IS TABULATED BELOW: IC50 Ex # Structure (uM)IUPAC names MS 223

+++++ N-(4-(3- cyclopentylpyrazin-2- yloxy)phenyl)benzo[d]thiazol-2-amine 389

TABLE (IXB) PREPARATION OF EXAMPLE 223 IS TABULATED BELOW: how differentfrom main Ex # Synthetic Scheme route reagent difference 223 30 120° C.

Example 2241-(4-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE

STEP 1. 2-FLUORO-3-IODOPYRAZINE

Butyl lithium solution (2.5 M in hexane, 881 mL, 2.01 mol) and 1.5 L ofdry THF were charged into a flame-dried 5.0 L round bottomed flask. Theflask was cooled to −50° C. and 2,2,6,6-tetramethylpiperidine (312.0 mL,2.20 mol) was added dropwise. The reaction mixture was warmed to 0° C.without taking the cold bath away and kept at that temperature for 20min. The reaction was then cooled to −78° C., and 2-fluoropyrazine (180g, 1.84 mol) in 150 mL of THF was added dropwise. The mixture was keptat −78° C. for 5 min. Iodine (464 g, 1.84 mol) in 500 mL of THF wasadded dropwise and the reaction mixture was kept at −78° C. for 1 h. Thereaction was quenched with the addition of 250 mL of concentrated HCl,250 mL MeOH and 250 mL THF at −78° C. The cold bath was then removed,and aqueous sodium bisulfite was added to get rid of traces of unreactediodine. The solvent was evaporated and the residue was diluted withwater and adjusted to pH 8. The mixture was extracted with ethyl acetate(3×1.5 L). Combined ethyl acetate layer was dried over sodium sulfateand concentrated. The crude product was purified by columnchromatography (Silica: 100-200 mess, solvent: 10% EtOAc/hexanes) togive the title compound as a white solid.

STEP 2: TERT-BUTYL 4-(3-FLUOROPYRAZIN-2-YL)PIPERIDINE-1-CARBOXYLATE

In an oven-dried 25 mLround bottomed flask was charged dry DMA (1 mL),zinc dust (0.430 g, 6.58 mmol). The mixture was stirred at RT while themixture of chlorotrimethylsilane (0.07 mL, 0.553 mmol) and1,2-dibromoethane (0.05 mL, 0.580 mmol) was added slowly. The resultingslurry was aged for 15 min. A solution of n-boc-4-iodo-piperidine (1.65g, 5.30 mmol) in DMA (2.6 mL) was added slowly to the above mixture.Zinc slurry reacted exothermically with the gradual addition of theiodide. After stirring for 30 min, the resulting milky solution wascooled to RT and used directly in the next step.

In an oven-dried flask were charged 2-fluoro-3-iodopyrazine (0.829 g,3.70 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloridepalladium(ii) complex with dichloramethane (0.091 g, 0.111 mmol),copper(i) iodide (0.042 g, 0.222 mmol), and DMA (3 mL). The resultingmixture was degassed with alternating vacuum/nitrogen purges. The(1-(tert-butoxycarbonyl)piperidin-4-yl)zinc(II) iodide (1.951 g, 5.18mmol) solution from previous step was filtered into the mixture. It wasdegassed one more time and then heated to 80° C. with stirring for 16 h.After cooling to RT, the reaction mixture was treated with methylbert-butylether (13 ml) and 1 N NH₄Cl (13 ml). The organic layer waspartitioned between EtOAc and 1 N NH₄Cl and the aqueous layer was backextracted with EtOAc (2×). The combined organic layer was washed withwater, brine, dried (Na₂SO₄) and concentrated. The crude material waschromatography through a Redi-Sep pre-packed silica gel column (40 g),eluting with a gradient of 0% to 20% EtOAc in hexane, to providetert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate as orangeoil. MS (ESI, pos. ion) m/z: 226.0 (M-56).

STEP 3. 1-(4-(3-FLUOROPYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE

To tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate (0.658 g,2.34 mmol) dissolved in DCM (5 mL) was added trifluoroacetic acid, 99%(1.39 mL, 18.7 mmol) dropwise. The reaction mixture was stirred at RTfor 1 h. The solvent was evaporated and to the residue was added DCM andthen evaporated. The process was repeated twice. The residue wasredissolved in DCM and treated with solid NaHCO₃. The mixture wasstirred for 1 h, filtered and concentrated. The orange oil was useddirectly in the following step.

To 2-fluoro-3-(piperidin-4-yl)pyrazine (0.311 g, 1.716 mmol) dissolvedin DCM (5 mL) was added triethylamine (0.286 mL, 2.06 mmol), then acetylchloride, reagent grade (0.134 mL, 1.89 mmol). The reaction mixture wasstirred at RT for 1 h then partitioned between DCM and water. Theaqueous layer was extracted with DCM (3×) and the combined organic layerwas washed with brine, dried (Na₂SO₄) and concentrated to give1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone as a yellow oil. MS(ESI, pos. ion) m/z: 224.0 (M-56).

STEP 4.1-(4-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE

The mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone(0.16 g, 0.67 mmol), 1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone(0.1 g, 0.45 mmol), and cesium carbonate (0.22 g, 0.67 mmol) in DMSO(1.5 mL) was heated at 80° C. for 20 h. After cooling to RT, thereaction mixture was partitioned between EtOAc and brine. The aqueouslayer was back extracted with EtOAc (2×) and the combined organic layerwas dried (Na₂SO₄) and concentrated. The crude material was purified bychromatography through a Redi-Sep pre-packed silica gel column (40 g),eluting with a gradient of 0% to 100% EtOAc in hexane, then 5% MeOH inEtOAc, to provide1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanoneas off-white solid. MS (ESI, pos. ion) m/z: 442.1 (M+1). IC50 (uM)+++++.

Example 2251-(4-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE

The mixture of 4-(benzo[d]thiazol-2-ylamino)phenol (91 mg, 0.38 mmol),1-(4-(3-fluoropyrazin-2-yl)piperidin-1-yl)ethanone (56 mg, 0.25 mmol),and cesium carbonate (123 mg, 0.38 mmol) in DMSO (0.85 mL) was heated at80° C. for 16 h. After cooling to RT, the reaction mixture waspartitioned between EtOAc and brine. The aqueous layer was backextracted with EtOAc (2×) and the combined organic layer was dried(Na₂SO₄) and concentrated. The crude material was purified bychromatography through a Redi-Sep pre-packed silica gel column (40 g),eluting with a gradient of 0% to 100% EtOAc in hexane, then 3% MeOH inEtOAc, followed by reverse-phase preparative HPLC using a Germini C18 5uM column, 0.1% TFA in CH₃CN/H₂O, gradient 10% to 100% over 15 min, thenneutralize with Si carbonate resin, to provide1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)as a white solid. MS (ESI, pos. ion) m/z: 445.9 (M+1). IC50 (uM) +++++.

Example 226(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(1-(2-FLUOROETHYL)PIPERIDIN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1. 2-FLUORO-3-(1-(2-FLUOROETHYL)PIPERIDIN-4-YL)PYRAZINE

In a glass microwave vial containing 2-fluoro-3-(piperidin-4-yl)pyrazine2,2,2-trifluoroacetate (0.2 g, 0.68 mmol), cesium carbonate (0.12 mL,1.5 mmol) was added 2-fluoroethyl tosylate (0.22 mL, 1.0 mmol) andAcetonitrile (2.5 mL). The reaction mixture was stirred and heated in aDiscover® model microwave reactor (CEM, Matthews, N C) at 120° C. for 10min (300 watts, Powermax feature on), then at the same temperature foranother 10 min. LCMS showed desired product formation 104960-15-1.

The reaction mixture was partitioned between EtOAc and water. Theaqueous layer was back extracted with EtOAc (3×) and the combinedorganic layer was washed with brine, dried (Na2SO4) and concentrated andused directly in the following step.

STEP 2.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(1-(2-FLUOROETHYL)PIPERIDIN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

The mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (78mg, 0.326 mmol), 2-fluoro-3-(1-(2-fluoroethyl)piperidin-4-yl)pyrazine(37 mg, 0.163 mmol), and cesium carbonate (106 mg, 0.326 mmol) in DMSO(0.5 mL) was heated at 80° C. for 20 h. The reaction mixture waspartitioned between EtOAc and brine. The aqueous layer was backextracted with EtOAc (3×) and the combined organic layer was dried(Na₂SO₄) and concentrated. The crude material was purified bychromatography through a Redi-Sep pre-packed silica gel column (40 g),eluting with a gradient of 0% to 100% EtOAc in hexane, followed byreverse-phase preparative HPLC using a Phenomenex Gemini column, 10micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH₃CN/H₂O, gradient 5% to 95%over 15 min then neutralization to provide(1H-benzo[d]imidazol-2-yl)(4-(3-(1-(2-fluoroethyl)piperidin-4-yl)pyrazin-2-yloxy)phenyl)as white solid. MS (ESI, pos. ion) m/z: 446.1 (M+1). IC50 (uM) +++++.

Example 227 METHYL4-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)PIPERIDINE-1-CARBOXYLATE

STEP 1. METHYL 4-(3-FLUOROPYRAZIN-2-YL)PIPERIDINE-1-CARBOXYLATE

To 2-fluoro-3-(piperidin-4-yl)pyrazine 2,2,2-trifluoroacetate (0.2 g,0.68 mmol) dissolved in DCM (2.5 mL) was added triethylamine (0.24 mL,1.7 mmol) and methyl chloroformate (63 uL, 0.81 mmol). The reactionmixture was stirred at RT under N2 for 2 h.

The reaction mixture was partitioned between saturated NaHCO₃ and DCM.The aqueous layer was back extracted with DCM (3×) and the combined DCMlayer was washed with brine, dried (Na₂SO₄) and concentrated to givemethyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate as orange oil.MS (ESI, pos. ion) m/z: 240.1 (M+1).

STEP 2. METHYL4-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)PIPERIDINE-1-CARBOXYLATE

The mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (112mg, 0.468 mmol), methyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate(56 mg, 0.23 mmol), and cesium carbonate (153 mg, 0.468 mmol) in DMSO(0.8 mL) was heated at 80° C. for 20 h. The reaction mixture waspartitioned between EtOAc and brine. The aqueous layer was backextracted with EtOAc (3×) and the combined organic layer was dried(Na₂SO₄) and concentrated. The crude material was purified bychromatography through a Redi-Sep pre-packed silica gel column (12 g),eluting with a gradient of 0% to 100% EtOAc in hexane, to provide methyl4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylateas white solid. MS (ESI, pos. ion) m/z: 458.1 (M+1). IC50 (uM) +++++.

Example 2281-(4-(3-(4-((1H-BENZO[D]IMIDAZOL-2-YL)(HYDROXY)METHYL)PHENOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE

To the solution of1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone(100 mg, 0.23 mmol) in THF (4.5 mL) was added palladium hydroxide, 20 wt% pd (dry basis) on carbon, wet, degussa type e101 ne/w (31.8 mg, 0.045mmol). The reaction mixture was stirred at RT under 1 atm of H₂ for 40h. The reaction mixture was filtered through a pad of celite and washedwith THF. The filtrate was washed with a mixture 1 N NaOH and brine. Theaqueous layer was extracted with EtOAc and MeOH (3×) and the combinedorganics were dried and concentrated. The crude material was purified byreverse-phase preparative HPLC using a Phenomenex Gemini column, 10micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH₃CN/H₂O, gradient 5% to 95%over 15 min then neutralization to provide1-(4-(3-(4-((1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanoneas white solid. MS (ESI, pos. ion) m/z: 444.0 (M+1). IC50 (uM) +++++.

Example 229(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(2-METHOXYPYRIDIN-3-YL)PYRAZIN-2-YLOXY)PHENYL)METHANOL

Same as the previous example to provide the compound. MS (ESI, pos. ion)m/z: 426.0 (M+1). IC50 (uM) +++++.

Example 230(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(PIPERIDIN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

STEP 1. TERT-BUTYL4-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)PIPERIDINE-1-CARBOXYLATE

To a 350 mL pressure vial is added tert-butyl4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate (200 mg, 0.711 mmol),Cs₂CO₃ (417 mg, 1.280 mmol), and(1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (305 mg, 1.280mmol) and N-methylpyrrolidinone (1.3 mL). The reaction was heated in themicrowave at 150° C. 1 h. The reaction was added to a flask containingH₂O (20 mL) with rapid stirring. The resulting slurry was filtered andthe solid filter cake washed with H₂O (3×5 mL). The solid was purifiedby ISCO (40 g SiO₂, 0-20% MeOH/CH₂Cl₂) to give tert-butyl4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylateas a brown solid.

STEP 2.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(PIPERIDIN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

To a flask containing tert-butyl4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate(230 mg, 0.460 mmol) is added chloroform (5 mL) and2,2,2-trifluoroacetic acid (0.709 mL, 9.21 mmol). The reaction wasstirred at rt 18 h. The solution was concentrated, followed byazeotropic removal of residual trifluoroacetic acid by concentrationfrom toluene (5 mL×2). The crude salt was freebased by dissolving inMeOH and application to a 5 g Bondesil-SCX ion exchange column. Elutionof the product with NH₃ in MeOH (2.0 M) and concentration of the productcontaining fractions gives(1H-benzo[d]imidazol-2-yl)(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)methanoneas a brown solid. MS (ESI, pos. ion) m/z: 400.0 (M+1). IC50 (uM) +++++.

Example 2311-(4-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)PERDEUTEROETHANONE

To a flask containing(1H-benzo[d]imidazol-2-yl)(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)methanone(60 mg, 0.150 mmol) is added dichloromethane (2 mL), triethylamine(0.021 mL, 0.150 mmol), Reactant 3 (10.16 μL, 0.180 mmol) and .HATU(57.1 mg, 0.150 mmol). After stirring for 16 hours, the reaction wasconcentrated and taken up in a minimum of MeOH. The solution waspurified by reverse-phase preparative HPLC to give1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)perdeuteroethanoneas a white solid. MS (ESI, pos. ion) m/z: 445.1 (M+1). IC50 (uM) +++++.

TABLE (XA) EXAMPLES 232 TO 248 ARE TABULATED BELOW: IC50 Ex # Structure(uM) IUPAC names MS 232

+++++ 1-(4-(3-(4-(1H- benzo[d]imidazole- 2- carbonyl)phenoxy) pyrazin-2-yl)piperidin-1-yl)-2- methoxyethanone 472 233

+++++ 1-(4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2-yl)piperidin- 1-yl)-2- methoxyethanone 476 234

+++++ 1-(4-(3-(4-(1H- benzo[d]imidazole- 2- carbonyl)phenoxy) pyrazin-2-yl)piperidin-1-yl)-2- fluoropropan-1-one 474 235

+++++ 1-(4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2-yl)piperidin- 1-yl)-2- fluoropropan-1-one 478.1 236

+++++ N-(4-(3-(1-(2- fluoroethyl)piperidin- 4-yl)pyrazin-2-yloxy)phenyl)benzo [d]thiazol-2-amine 450.0 237

+++++ N-(4-(3-(1- methylpiperidin-4- yl)pyrazin-2- yloxy)phenyl)benzo[d]thiazol-2-amine 418.1 238

+++++ 1-(4-(3-(4-(1H- benzo[d]imidazole- 2- carbonyl)phenoxy) pyrazin-2-yl)piperidin-1-yl)-1- oxopropan-2-yl acetate 514.1 239

+++++ 1-(4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2-yl)piperidin- 1-yl)-2- hydroxypropan-1- one 476.1 240

+++++ 1-(3-(3-(4-(1H- benzo[d]imidazole- 2- carbonyl)phenoxy) pyrazin-2-yl)pyrrolidin-1- yl)ethanone 428.1 241

+++++ 1-(3-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy) pyrazin-2-yl)pyrrolidin-1- yl)ethanone 432.0 242

+++++ 1-(4-(3-(4-(1- methyl-1H- benzo[d]imidazole- 2- carbonyl)phenoxy)pyrazin-2- yl)piperidin-1- yl)ethanone 456.0 243

+++++ 2-methoxy-1-(4-(3- (4-(1-methyl-1H- benzo[d]imidazole- 2-carbonyl)phenoxy) pyrazin-2- yl)piperidin-1- yl)ethanone 486.0 244

+++++ 2-(4-(3-(4-(1H- benzo[d]imidazole- 2- carbonyl)phenoxy) pyrazin-2-yl)piperidin-1-yl)-2- oxoethyl acetate 500.1 245

+++++ 1-(4-(3-(4-(1H- benzo[d]imidazole- 2- carbonyl)phenoxy) pyrazin-2-yl)piperidin-1-yl)-2- (dimethylamino) ethanone 485.1 246

+++++ 1-(4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2-yl)piperidin- 1-yl)-2- (dimethylamino) ethanone 489.0 247

+++++ 3-(4-(3-(4-(1H- (benzo[d]imidazole- 2- carbonyl)phenoxy)pyrazin-2- yl)piperidin-1-yl)-3- oxopropanenitrile 467.1 248

+++++ 1-(4-(3-(4- (benzo[d]thiazol-2- ylamino)-2- fluorophenoxy)pyrazin-2-yl)piperidin- 1-yl)ethanone 464.4

VER

TABLE (XB) PREPARATION OF EXAMPLES 232 TO 248 ARE TABULATED BELOW:Synthetic How Different from Ex # Scheme Main Route Reagent Difference232 and 233 33 Same

234 and 235 33 O-(-7- azabenzotriazol-1- yl)-n, ′n, ′n, ′n′-tetramethyluronium- hexafluorophosphate Et₃N

236 33 Cs₂CO₃, CH₃CN Microwave, 120° C.

237 33 AcOH, HCHO NaBH(OAc)₃ 238 and 239 33 O-(-7- azabenzotriazol-1-yl)-n, ′n, ′n, ′n′- tetramethyluronium- hexafluorophosphate Et₃N

240 and 241 33 Same

242 4 Same

243 4 Same

244 33 Same

245 and 246 33 Same

247 33 O-(-7- azabenzotriazol-1- yl)-n, ′n, ′n, ′n′- tetramethyluronium-hexafluorophosphate Et₃N

248 5, 33 Heated reaction to 150° C. (scheme 5). Heated reaction to 140°C. (scheme 32).

Example 2491-(4-(3-(6-(BENZO[D]THIAZOL-2-YLAMINO)PYRIDIN-3-YLOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE

STEP 1.1-(4-(3-(6-CHLOROPYRIDIN-3-YLOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE

To a mixture of cesium carbonate (0.505 g, 1.55 mmol),1-(4-(3-chloropyrazin-2-yl)piperidin-1-yl)ethanone (0.129 g, 0.538mmol), and 6-chloropyridin-3-ol (0.140 g, 1.08 mmol) was added NMP (2mL). The reaction mixture was degassed and heated to 130° C. for 2 h.The reaction mixture was diluted with EtOAc. The organic phase waswashed with water (1×), brine (1×), dried over MgSO₄, filtered, andconcentrated. Purification by flash column chromatography on silica gel(50% to 100% EtOAc (10% MeOH) in hexanes) gave1(4-(3-(6-chloropyridin-3-yloxy)pyrazin-2-yl)piperidin-1-yl)ethanone asa colorless oil that was used in the next step without furtherpurification. MS (ESI, pos. ion) m/z: 333.2 (M+1).

STEP 2.1-(4-(3-(6-(BENZO[D]THIAZOL-2-YLAMINO)PYRIDIN-3-YLOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE

To a mixture of tris(dibenzylideneacetone)dipalladium(0) (0.021 g, 0.023mmol), Na₂CO₃ (0.081 g, 0.76 mmol),9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine (0.040 g, 0.069mmol), benzo[d]thiazol-2-amine (0.110 g, 0.732 mmol), and1-(4-(3-(6-chloropyridin-3-yloxy)pyrazin-2-yl)piperidin-1-yl)ethanone(0.182 g, 0.547 mmol) was added PhMe (3 mL). The reaction mixture wasdegassed and heated to 100° C. for 40 h. The reaction mixture wasdiluted with EtOAc and the organic phase was washed with water (1×),brine (1×), dried over MgSO₄, filtered, and concentrated. Purificationby flash column chromatography on silica gel (10% to 80% EtOAc (10%MeOH) in hexanes) gave1-(4-(3-(6-(benzo[d]thiazol-2-ylamino)pyridin-3-yloxy)pyrazin-2-yl)piperidin-1-yl)ethanoneas a white solid. MS (ESI, pos. ion) m/z: 447.2 (M+1). IC50 (uM) ++.

Example 2501-(3-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)AZETIDIN-1-YL)ETHANONE

STEP 1. TERT-BUTYL 3-(3-CHLOROPYRAZIN-2-YL)AZETIDINE-1-CARBOXYLATE

To a flame dried 25 mL flask with zinc dust (217 mg, 3.31 mmol) andN,N-dimethylacetamide (2 mL) was added chlorotrimethylsilane (33.5 μL,0.265 mmol) and 1,2-dibromoethane (22.83 μL, 0.265 mmol). The resultingslurry was stirred 15 min, then tert-butyl 3-iodoazetidine-1-carboxylate(753 mg, 2.66 mmol) was added to the above mixture (mild exotherm). Thesuspension was stirred at rt 30 min.

The zinc solution was added via syringe to a solution of2,3-dichloropyrazine (277 mg, 1.862 mmol), (dppf)PdCl₂-CH₂Cl₂ (65.2 mg,0.080 mmol), and copper(I) iodide (30.4 mg, 0.160 mmol) inN,N-dimethylacetamide (1.0 mL) that was degassed with N₂ (3×). Thesolution was heated to 80° C. and stirred 1 h. The reaction was quenchedwith NH₄Cl (10 mL) and extracted with EtOAc (3×10 mL). The combinedorganic fractions were dried (MgSO₄), concentrated, and purified by ISCO(40 g SiO₂, 10-100% EtOAc/Hexane) to give tert-butyl3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (262 mg, 0.971 mmol,36.5% yield) as a clear, colorless oil.

STEP 2. TERT-BUTYL3-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)AZETIDINE-1-CARBOXYLATE

To a vial with tert-butyl3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (100 mg, 0.371 mmol),(1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (265 mg, 1.112mmol) and cesium carbonate (362 mg, 1.112 mmol) under N₂ is added DMSO(1.0 mL). The reaction is heated to 120° C. in an oil bath 1 h. Thereaction was cooled to rt, added to H₂O (5 mL), and extracted with EtOAc(3×5 mL). The combined organic layers were dried (MgSO₄) andconcentrated to give tert-butyl3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidine-1-carboxylate(175 mg) as a yellow oil which was carried on to the next step withoutpurification.

STEP 3.(4-(3-(AZETIDIN-3-YL)PYRAZIN-2-YLOXY)PHENYL)(1H-BENZO[D]IMIDAZOL-2-YL)METHANONE

To a solution of tert-butyl3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidine-1-carboxylate(175 mg, 0.371 mmol) in CH₂Cl₂ (1 mL) is added 2,2,2-trifluoroaceticacid (1.0 mL). The reaction was stirred at rt 1 h. The solution wasconcentrated and CH₂Cl₂ (5 mL) and saturated NaHCO₃ (0.5 mL) was added.MgSO₄ was added to remove water and the solution filtered andconcentrated to give the crude amine as a dark green oil which wascarried on to the next step without purification. (Note: An insolublesolid crashed out during the extraction, which later was identified asthe desired crude amine product, which is sparingly soluble in CH₂Cl₂,but soluble in THF. The insoluble solid from the extraction wasdissolved in THF, dried (MgSO₄), concentrated, and combined with thematerial from aqueous extraction and carried on into the next step.

STEP 4.1-(3-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)AZETIDIN-1-YL)ETHANONE

To a solution of(4-(3-(azetidin-3-yl)pyrazin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanonein DMF (1.0 mL) is added triethylamine (104 μL, 0.743 mmol) and1-(1H-imidazol-1-yl)ethanone (60.0 mg, 0.545 mmol). The reaction wasstirred at rt 7 h. The reaction mixture was added to saturated NaHCO₃ (5mL) and extracted with EtOAc (3×5 mL). The combined organic layers werewashed with water (5 mL), saturated NaCl (5 mL), dried (MgSO₄) andconcentrated. Purification by RPHPLC gives1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidin-1-yl)ethanone(55.4 mg, 36.0% over 3 steps) as a white solid. MS (ESI, pos. ion) m/z:414.0 (M+1). IC50 (uM) +++++.

Example 2511-(3-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE

STEP 1. 1-ACETYL-1,4,5,6-TETRAHYDROPYRIDIN-3-YLTRIFLUOROMETHANESULFONATE

To a −78° C. solution of diisopropylamine (3.60 mL, 25.5 mmol) in THF(30 mL) was added butyllithium (9.35 mL, 23.38 mmol) dropwise. After theaddition was complete the reaction was allowed to stir at −78° C. for 15minutes, then a solution of 1-acetylpiperidin-3-one (3.0 g, 21.25 mmol)in THF (5 mL) was added dropwise. After a further 20 minutes, a solutionof1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(8.35 g, 23.38 mmol) in THF (15 mL) was added dropwise to the reaction.The solution was allowed to slowly warm to room temperature. After 16hours, the reaction was quenched with sat'd NH₄Cl and the diluted withwater (20 mL). The aqueous solution was basified and extracted withEtOAc (4×30 mL). The combined organics were washed with brine andconcentrated in vacuo. The crude product was adsorbed onto a plug ofsilica gel and chromatographed through a Redi-Sep® pre-packed silica gelcolumn (40 g), eluting with 0% to 70% EtOAc in hexane, to provide1-acetyl-1,4,5,6-tetrahydropyridin-3-yl trifluoromethanesulfonate as agolden oil. [M+1]=274.0.

STEP 2.1-(5-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-3,4-DIHYDROPYRIDIN-1(2H)-YL)ETHANONE

To a solution of 1-acetyl-1,4,5,6-tetrahydropyridin-3-yltrifluoromethanesulfonate (2.5 g, 9.15 mmol), bis(pinacolato)diboron(2.88 g, 11.34 mmol), potassium acetate (1.91 g, 19.46 mmol), anddioxane (60 mL) was added 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(ii) dichloromethane complex (400 mg, 0.547 mmol). The mixturewas purged with nitrogen and then was heated to 80° C. After 16 hours,the reaction was cooled to room temperature. The mixture was dilutedwith 150 mL of EtOAc and washed with 50 mL of water and 50 mL of brine,dried over MgSO₄, and concentrated in vacuo. The crude product wasadsorbed onto a plug of silica gel and chromatographed through aRedi-Sep® pre-packed silica gel column (40 g), eluting with 0% to 40%EtOAc in hexane, to provide1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridin-1(2H)-yl)ethanoneas an orange oil. [M+1]=252.1.

STEP 3. TERT-BUTYL5-(3-(4-(METHOXYCARBONYL)PHENOXY)PYRAZIN-2-YL)-3,4-DIHYDROPYRIDINE-1(2H)-CARBOXYLATE

To a mixture of (amphos)₂PdCl₂ (0.145 g, 0.205 mmol), potassium acetate(1.045 g, 10.65 mmol), methyl 4-(3-chloropyrazin-2-yloxy)benzoate (1.084g, 4.10 mmol), and tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate(1.900 g, 6.14 mmol) under N₂ was added MeCN (7.0 mL) and Ar degassedwater (0.70 mL). The reaction mixture was degassed with Ar (10 min) thenheated to 80° C. for 20 h. The reaction mixture was diluted with H₂O (20mL) and extracted with EtOAc (2×10 mL). The combined organic extractswere washed with brine (10 mL), dried (MgSO₄), and concentrated.Purification by ISCO (120 g SiO₂, 10-100% EtOAc/hexanes) gave tert-butyl5-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylateas a yellow oil.

STEP 4. TERT-BUTYL3-(3-(4-(METHOXYCARBONYL)PHENOXY)PYRAZIN-2-YL)PIPERIDINE-1-CARBOXYLATE

To a rb flask containing tert-butyl5-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate(900 mg, 2.187 mmol) and palladium on carbon (233 mg, 0.219 mmol) (10 wt%) under N₂ is added THF (5.5 mL) and EtOH (5.5 mL). The flask is purgedwith H₂ (3×), then stirred under H₂ at rt 3 h. The reaction was filteredthrough celite and the filter cake washed with EtOAc (2×10 mL). Thecombined filtrates were concentrated and the residue purified by ISCO(12 g SiO₂, 0-50% EtOAc/Hexane) to give tert-butyl3-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylateas a brown solid.

STEP 5.(1H-BENZO[D]IMIDAZOL-2-YL)(4-(3-(PIPERIDIN-3-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE

To a solution of 1-(diisopropoxymethyl)-1H-benzo[d]imidazole (306 mg,1.233 mmol) in THF (5 mL) at 0° C. is added LiHMDS (1.233 mL, 1.233mmol) over 1 min. The reaction was stirred 5 min., then 1 mL of the 6.5mL solution (0.5 theoretical equivalent of the lithium benzoimidazole)was added to a solution of tert-butyl3-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate(170 mg, 0.411 mmol) in THF (2 mL) at 0° C. The reaction was stirred at0° C. 30 min. LCMS showed 59% conversion. An additional 1 mL of lithiumbenzoimidazole solution (0.5 equivalents) was added and the reactionstirred 5 min. at 0° C. The reaction was quenched with HCl (2 mL, 4 M in1,4-dioxane), MeOH was added, and the reaction warmed to rt and stirred2 h, the reaction was concentrated to give the crude aminehydrochloride, which was taken on to the next step without purification.

STEP 6.1-(3-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)PIPERIDIN-1-YL)ETHANONE2,2,2-TRIFLUOROACETATE

To the crude amine in DMF (1.0 mL) is addedN-ethyl-N-isopropylpropan-2-amine (0.280 mL, 1.643 mmol) and1-(1H-imidazol-1-yl)ethanone (56.5 mg, 0.513 mmol). The reaction wasstirred at rt 5 h. The reaction mixture was added to saturated NaHCO₃ (5mL) and extracted with EtOAc (3×5 mL). The combined organic layers werewashed with water (5 mL), saturated NaCl (5 mL), dried (MgSO₄) andconcentrated to give the crude product. Purification by RPHPLC gives1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone2,2,2-trifluoroacetate (9 mg, 0.016 mmol, 3.95% yield) as a racemicmixture of enantiomers. MS (ESI, pos. ion) m/z: 442.1 (M+1). IC50 (uM)+++++.

Example 2524-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)-1-METHYL-5,6-DIHYDROPYRIDIN-2(1H)-ONE

STEP 1. ETHYL 3-(BENZYL(METHYL)AMINO)PROPANOATE

A solution of ethyl acrylate (6.51 mL, 59.9 mmol) andN-benzylmethylamine (8.48 mL, 65.9 mmol) in ethanol (33.3 mL) wasstirred at room temperature for 18 h. The reaction was diluted withEtOAc and washed with aqueous saturated NaHCO₃ solution. The organiclayer was dried (MgSO₄), filtered, and concentrated in vacuo. Flashcolumn chromatography (10% to 50% EtOAc/Hexanes) provided ethyl3-(benzyl(methyl)amino)propanoate as a colorless oil. [M+1]=222.1.

STEP 2. ETHYL 3-(METHYLAMINO)PROPANOATE

A solution of ethyl 3-(benzyl(methyl)amino)propanoate (3 g, 13.56 mmol)in ethanol (67.8 mL) was added palladium, 10 wt. % on carbon (0.3 g,0.282 mmol) and hydrogenated (double-walled balloon pressure) at roomtemperature for 3 h. The reaction mixture was filtered via a pad ofCelite, and the filtrate was concentrated in vacuo to give ethyl3-(methylamino)propanoate (1.12 g, 63.0% yield) as a light golden yellowoil.

STEP 3. ETHYL 3-((3-ETHOXY-3-OXOPROPYL)(METHYL)AMINO)-3-OXOPROPANOATE

A solution of ethyl 3-(methylamino)propanoate (1.12 g, 8.54 mmol) andtriethylamine (1.425 mL, 10.25 mmol) in dichloromethane (42.7 mL) underargon was cooled to 0° C. and added ethyl malonoyl chloride (1.182 mL,9.39 mmol). The resulting yellow solution was allowed to warm to roomtemperature and stirred for 1 h. The reaction was diluted with CH₂Cl₂and washed with aqueous saturated NaHCO₃ solution; the aqueous layer wasback-extracted with CH₂Cl₂ (1×). The combined organic extracts weredried (MgSO₄), filtered, and concentrated in vacuo. Flash columnchromatography (10% to 50% EtOAc/Hexanes) afforded ethyl3-((3-ethoxy-3-oxopropyl)(methyl)amino)-3-oxopropanoate as a cleargolden oil. [M+1]=246.2.

STEP 4. 1-METHYLPIPERIDINE-2,4-DIONE

Into a 50-mL round bottomed flask was added ethanol (4 mL) under argon,followed by sodium (0.121 g, 5.25 mmol). The mixture was stirred at roomtemperature for 15 min, during which a solution of ethyl3-((3-ethoxy-3-oxopropyl)(methyl)amino)-3-oxopropanoate (1.17 g, 4.77mmol) in ethanol (5 mL) was added. The resulting clear, colorlessmixture was heated at 80° C. for 1 h, during which LC-MS indicatedcompletion of reaction and a clean conversion to the desired ethyl1-methyl-2,4-dioxopiperidine-3-carboxylate intermediate. Upon cooling toroom temperature, the reaction was diluted with Et₂O, resulting in theformation of a white precipitate (desired product). The whiteprecipitate was collected via filtration, taken up in 5% aqueous HClsolution (8 mL), and refluxed for 1 h. The cooled mixture was extractedwith CH₂Cl₂ (5×) and the combined organic extracts were dried (MgSO₄),filtered, and concentrated in vacuo. Flash column chromatography (20%EtOAc/Hexanes to 100% EtOAc) afforded 1-methylpiperidine-2,4-dione as aviscous milky oil. [M+1]=128.1.

STEP 5. 1-METHYL-6-OXO-1,2,3,6-TETRAHYDROPYRIDIN-4-YLTRIFLUOROMETHANESULFONATE

A solution of 1-methylpiperidine-2,4-dione (0.295 g, 2.320 mmol) andpyridine (0.378 mL) in dichloromethane (14.50 mL) under argon was cooledto −78° C. and added trifluoromethanesulfonic anhydride (0.468 mL, 2.78mmol). After stirring at −78° C. for 10 min, the reaction was warmed to0° C. and stirred for 1 h. The mixture was quenched with aqueoussaturated NH₄Cl solution and extracted with CH₂Cl₂; the aqueous layerwas back-extracted with CH₂Cl₂ (2×). The combined organic extracts weredried (MgSO₄), filtered, and concentrated in vacuo. Flash columnchromatography on basic alumina (10% to 50% EtOAc/Hexanes) gave1-methyl-6-oxo-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonateas a colorless oil. [M+1]=260.0.

STEP 6.1-METHYL-4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)-5,6-DIHYDROPYRIDIN-2(1H)-ONE

1-Methyl-6-oxo-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate(0.56 g, 2.160 mmol), bis(pinacolato)diboron (0.658 g, 2.59 mmol),1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.141 g,0.173 mmol), potassium acetate (0.424 g, 4.32 mmol) and 1,4-dioxane (7.2mL) were combined in a sealed tube and heated at 80° C. for 18 h. Thecooled reaction was diluted with CH₂Cl₂ and washed with aqueoussaturated NaHCO₃ solution; the aqueous layer was back-extracted withCH₂Cl₂ (1×). The combined organic extracts were dried (MgSO₄), filtered,and concentrated in vacuo. Flash column chromatography (1% to 10%MeOH/CH₂Cl₂) provided1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-2(1H)-oneas a brown solid. [M+1]=156.1 (for boronic acid).

STEP 7.4-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)-1-METHYL-5,6-DIHYDROPYRIDIN-2(1H)-ONE

1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-2(1H)-one(0.365 g, 1.539 mmol),(1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone(0.540 g, 1.539 mmol),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(0.076 g, 0.108 mmol), potassium acetate (0.453 g, 4.62 mmol), and 9:1dioxane-H₂O (7.5 mL) were combined in a sealed tube and heated at 100°C. for 3 h. The cooled reaction was diluted with CH₂Cl₂ and washed withwater; the aqueous layer was back-extracted with CH₂Cl₂ (1×). Theorganic extracts were combined, dried (MgSO₄), filtered, andconcentrated in vacuo. Flash column chromatography (1% to 5%MeOH/CH₂Cl₂) provided a crude crop of the desired product. Furthertrituration with MeOH afforded4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methyl-5,6-dihydropyridin-2(1H)-oneas a yellow amorphous solid. [M+1]=426.8. IC50 (uM) +++++.

Example 2534-(3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZIN-2-YL)-1-METHYLPIPERIDIN-2-ONE

A solution of4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methyl-5,6-dihydropyridin-2(1H)-one(0.0687 g, 0.161 mmol) (Step 7, Example 252) in 1:1 EtOH-dioxane (8 mL)was added palladium, 10% wt. on activated carbon (0.007 g, 6.58 μmol)and hydrogenated (double-walled balloon pressure) at room temperaturefor 24 h. The reaction mixture was filtered via a pad of Celite, and thefiltrate was concentrated in vacuo and purified via flash columnchromatography (20% to 80% EtOAc (10% MeOH)/Hexanes) to give4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methylpiperidin-2-one(0.0262 g, 38.0% yield) as a light yellow amorphous solid. MS (ESI, pos.ion) m/z: 428.9 (M+1). IC50 (uM) +++++.

Example 2543-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)-N-PHENETHYLPYRAZINE-2-CARBOXAMIDE

STEP 1. ETHYL 3-(4-(1H-BENZO[D]IMIDAZOLE-2CARBONYL)PHENOXY)PYRAZINE-2-CARBOXYLATE

In a 2 L autoclave was added a solution(1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone(5.0 g, 14.2 mmol) in ethanol (150 mL), followed by dppf (0.273 g, 0.42mmol), palladium acetate (25 mg, 0.11 mmol) and sodium acetate (4.65 g,56.8 mmol). The autoclave was applied CO(g) 15 kg/cm2 pressure. Then thereaction mixture was heated to 135° C. and maintained at thattemperature for 1 h. After cooling to RT, the reaction mixture wasconcentrated and diluted with water, then extracted by ethyl acetate(3×200 mL). The combined organic extracts were dried over sodium sulfateand concentrate under vacuum to give a dark brown solid which was useddirectly in the following step. MS [M+H]=389.1.

STEP 2.3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)PYRAZINE-2-CARBOXYLIC ACID

To the solution of ethyl 3-(4-(1H-benzo[d]imidazole-2carbonyl)phenoxy)pyrazine-2-carboxylate (30 g, 77 mmol) in methanol (250mL) was added aqueous NaOH solution (4.62 g, 115 mmol) in 50 mL ofwater. The reaction mixture was heated to reflux for 1 h. The reactionmixture was concentrated then diluted with water. The aqueous layer waswashed with ethyl acetate and then acidified by addition of 2N HCl to pH6. The precipitate was collected by filtration, dried to give the titlecompound as a light brown solid. MS [M+H]=351.2.

STEP 3.3-(4-(1H-BENZO[D]IMIDAZOLE-2-CARBONYL)PHENOXY)-N-PHENETHYLPYRAZINE-2-CARBOXAMIDE

HATU (123 mg, 0.324 mmol) was added to a mixture of3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazine-2-carboxylic acid(106 mg, 0.294 mmol) and diisopropylethylamine (102 μL, 0.588 mmol) inDMF (1 mL) and the mixture was stirred at RT for 10 min.2-Phenylethylamine (55.8 μL, 0.441 mmol) was added and the mixture wasstirred at RT for 1 h. The mixture was purified by chromatography onsilica gel to deliver3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-phenethylpyrazine-2-carboxamideas a white solid. MS (ESI, pos. ion) m/z: 464.0 (M+1). IC50 (uM) +++++.

TABLE (XIA) EXAMPLES 255 TO 260 ARE TABULATED BELOW: IC50 Ex # Structure(uM) IUPAC names MS 255

+++++ 3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)-N- (4-(trifluoromethyl) phenethyl)pyrazine-2- carboxamide 532 256

++++ (S)-3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)-N-(1-methoxypropan-2- yl)pyrazine-2- carboxamide 432 257

+++++ 3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)-N- (2-(pyridin-2-yl)ethyl)pyrazine-2- carboxamide 465 258

++++ 3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)-N- (2-hydroxyethyl)pyrazine- 2-carboxamide 404 259

+++++ (rac)-3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)-N-(1-(pyridin-2-yl)propan- 2-yl)pyrazine-2- carboxamide 479 260

+++++ 3-(4-(1H- benzo[d]imidazole-2- carbonyl)phenoxy)-N- (1-benzylcyclopropyl) pyrazine-2-carboxamide 490

TABLE (XIB) PREPARATION OF EXAMPLES 255 TO 260 ARE TABULATED BELOW: HowDifferent Ex Synthetic from Main # Scheme Route Reagent Difference 25540 Same

256 40 Same

257 40 Same

258 40 Same

259 40 Same

260 40 Same

Table (XIIA): Examples 261 to 280 are Tabulated Below.

The racemic mixtures were/can be separated by chiral HPLC to give thefollowing chiral compounds by known methods. Prep* means preparativeexperiment was performed according to the tabulated previous examples.

Ex. IC50 No Structure (uM) Prep* IUPAC names MS 261

+++++ See ex. 40 (R)-1-(3-(4-(1H- benzo[d]imidazole- 2-carbonyl)phenoxy) pyrazin-2- yl)pyrrolidine-3- carbonitrile 411 262

+++++ See ex. 40 (S)-1-(3-(4-(1H- benzo[d]imidazole- 2-carbonyl)phenoxy) pyrazin-2- yl)pyrrolidine-3- carbonitrile 411 263

+++++ See ex.43 (R)-ethyl 1-(3-(4- (1H- benzo[d]imidazole- 2-carbonyl)phenoxy) pyrazin-2- yl)piperidine-3- carboxylate 472 264

+++++ See ex. 43 (S)-ethyl 1-(3-(4- (1H- benzo[d]imidazole- 2-carbonyl)phenoxy) pyrazin-2- yl)piperidine-3- carboxylate 472 265

+++++ See ex. 42 (S)-methyl 1-(3-(4- (1H- benzo[d]imidazole- 2-carbonyl)phenoxy) pyrazin-2- yl)pyrrolidine-3- carboxylate 444 266

+++++ See ex. 42 (R)-methyl 1-(3-(4- (1H- benzo[d]imidazole- 2-carbonyl)phenoxy) pyrazin-2- yl)pyrrolidine-3- carboxylate 444 267

+++++ See ex. 94 (R)-4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2-yl)-6- methylpiperazin-2- one 433 268

+++++ See ex. 94 (S)-4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2-yl)-6- methylpiperazin-2- one 433 269

+++++ See ex. 189 (1H- benzo[d]imidazol-2- yl)(4-(3-((1R,3S)-3-hydroxycyclohexyl) pyrazin-2- yloxy)phenyl) methanone 415 270

+++++ See ex. 189 (1H- benzo[d]imidazol-2- yl)(4-(3-((1S,3R)-3-hydroxycyclohexyl) pyrazin-2- yloxy)phenyl) methanone 415 271

+++++ See ex. 191 (1S,3R)-3-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2- yl)cyclohexanol 419 272

+++++ See ex. 191 (1R,3S)-3-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2- yl)cyclohexanol 419 273

+++++ See ex. 190 (1H- benzo[d]imidazol-2- yl)(4-(3-((1S,3S)-3-hydroxycyclohexyl) pyrazin-2- yloxy)phenyl) methanone 415 274

+++++ See ex. 190 (1H- benzo[d]imidazol-2- yl)(4-(3-((1R,3R)-3-hydroxycyclohexyl) pyrazin-2- yloxy)phenyl) methanone 415 275

+++++ See ex. 192 (1S,3S)-3-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2- yl)cyclohexanol 419 276

+++++ See ex. 192 (1R,3R)-3-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2- yl)cyclohexanol 419 277

+++++ See ex. 234 (R)-1-(4-(3-(4-(1H- benzo[d]imidazole- 2-carbonyl)phenoxy) pyrazin-2- yl)piperidin-1-yl)-2- fluoropropan-1-one474 278

+++++ See ex. 234 (S)-1-(4-(3-(4-(1H- benzo[d]imidazole- 2-carbonyl)phenoxy) pyrazin-2- yl)piperidin-1-yl)-2- fluoropropan-1-one474 279

+++++ See ex. 235 (R)-1-(4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2-yl)piperidin- 1-yl)-2- fluoropropan-1-one 478 280

+++++ See ex. 235 (S)-1-(4-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2-yl)piperidin- 1-yl)-2- fluoropropan-1-one 478 281

+++++ See ex. 194 (R)-3-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2- yl)cyclohexanone 417 282

+++++ See ex. 194 (S)-3-(3-(4- (benzo[d]thiazol-2- ylamino)phenoxy)pyrazin-2- yl)cyclohexanone 417

BIOLOGICAL EXAMPLES Example 1 MPDE10A7 ENZYME ACTIVITY AND INHIBITION

Enzyme Activity. An IMAP TR-FRET assay was used to analyze the enzymeactivity (Molecular Devices Corp., Sunnyvale Calif.). 5 μL of serialdiluted PDE10A (BPS Bioscience, San Diego, Calif.) or tissue homogenatewas incubated with equal volumes of diluted fluorescein labeled cAMP orcGMP for 60 min in 384-well polystyrene assay plates (Corning, Corning,N.Y.) at room temperature. After incubation, the reaction was stopped byadding 60 μL, of diluted binding reagents and was incubated for 3 hoursto overnight at room temperature. The plates were read on an Envision(Perkin Elmer, Waltham, Mass.) for time resolved fluorescence resonanceenergy transfer. The data were analyzed with GraphPad Prism (La Jolla,Calif.).

Enzyme Inhibition. To check the inhibition profile, 5 μL, of serialdiluted compounds were incubated with 5 μL, of diluted PDE10 enzyme (BPSBioscience, San Diego, Calif.) or tissue homogenate in a 384-wellpolystyrene assay plate (Corning, Corning, N.Y.) for 30 min at roomtemperature. After incubation, 10 μL, of diluted fluorescein labeledcAMP or cGMP substrate were added and incubated for 60 min at roomtemperature. The reaction was stopped by adding 60 μL, of dilutedbinding reagents and plates were read on an Envision (Perkin Elmer,Waltham, Mass.) for time resolved fluorescence resonance energytransfer. The data were analyzed with GraphPad Prism (La Jolla, Calif.).

Exemplary compounds of the invention having useful activity as measuredby IC50 are shown in Table XIII below. The tabulated IC50 data representan average IC50 data for each compound.

TABLE XIII Average IC50 Structure MS (μM)

401.424 0.0156

350.764 0.287

415.451 0.00873

429.478 0.0158

419.507 0.00817

419.463 0.00216

433.534 0.00944

448.549 0.00844

354.82 0.603

433.49 0.0084

414.491 0.0033

418.475 0.502

407.431 0.00567

360.371 0.046

447.517 0.023

433.534 0.0217

482.541 0.0128

419.507 0.00289

484.557 0.027

417.427 0.0175

447.561 0.00955

447.561 0.0185

447.561 0.06

401.424 0.0076

426.498 0.0961

447.561 0.0395

433.534 0.00808

433.534 0.0226

428.45 0.00216

415.451 0.00112

398.42 0.00336

433.534 0.000117

418.479 0.00641

411.487 0.0175

439.473 0.00116

400.436 0.000486

461.402 0.242

393.405 0.00805

393.405 0.0075

417.427 0.042

415.451 0.00254

450.452 0.033

422.442 0.036

452.476 0.00603

436.425 0.00206

482.566 0.078

481.578 1.07

411.487 0.0113

436.497 0.076

460.56 0.0127

433.534 0.037

415.451 0.00205

429.478 0.00137

443.505 0.004

424.462 0.00679

398.42 0.0161

410.435 0.00132

400.464 0.00675

422.471 0.0638

398.449 0.0129

432.506 0.00464

400.436 0.00259

428.474 0.0232

461.544 0.0678

412.447 0.00169

471.515 0.00519

443.461 0.00343

471.515 0.000773

402.412 0.0116

360.328 0.556

431.906 0.0146

464.483 0.00808

414.463 0.000426

414.463 0.00104

443.464 0.00359

467.487 0.00373

431.45 0.0454

443.464 0.00318

427.486 0.00412

447.561 0.00461

401.424 0.00512

531.492 0.0246

443.505 0.000749

426.474 0.004

443.461 0.00118

368.754 1.58

351.752 0.171

443.505 0.00186

403.396 0.0655

478.51 0.00472

429.478 0.00032

447.52 0.0144

489.533 0.000575

397.461 0.0104

457.531 0.029

372.81 0.751

463.495 0.00447

410.435 0.00176

410.435 0.00132

471.515 0.0108

471.515 0.000843

372.81 >30

372.81 0.538

432.506 0.00305

432.506 0.0171

372.81 0.614

443.461 0.00421

443.461 0.00135

428.45 0.00257

390.465 0.00203

346.345 0.0436

374.398 0.0566

388.425 0.0262

386.409 0.164

414.342 0.187

390.397 0.0291

423.43 1.71

408.415 2.12

409.404 0.0515

384.393 0.673

457.512 0.00186

416.435 0.00556

445.477 0.0895

429.478 0.541

403.44 0.486

443.505 0.235

423.43 0.014

437.457 0.00805

451.484 0.0109

432.428 0.0142

387.441 0.000101

404.492 0.000606

402.452 0.386

423.43 0.000321

429.502 0.00446

425.446 0.0025

561.66 0.245

418.519 0.0118

462.528 0.00628

422.482 0.000661

422.433 0.0529

414.463 0.00131

533.65 0.251

423.43 0.0142

422.482 0.00264

338.365 0.777

399.408 0.0317

338.365 0.803

422.482 0.0118

338.365 12.5

423.43 0.00756

404.492 0.00243

427.486 0.00367

418.519 0.00232

441.489 0.000182

401.424 0.00772

414.463 0.00102

445.545 0.000059

418.519 0.00157

437.457 0.000594

364.791 0.187

414.463 0.00125

414.463 0.00136

387.397 0.00694

420.491 0.000902

418.519 0.00133

423.43 0.0388

374.398 0.0252

376.462 0.814

414.463 0.00116

416.435 0.00216

414.463 0.000961

418.519 0.00222

412.447 0.000199

418.519 0.00254

418.519 0.00134

414.463 0.000992

414.463 0.00112

438.485 0.166

423.43 0.00542

427.486 0.0122

440.501 0.0418

440.501 0.154

425.446 0.00186

428.49 0.000748

428.49 0.00142

418.426 0.00183

413.435 0.00271

427.462 0.00602

422.482 0.0122

411.395 0.00353

414.463 0.00122

441.42 0.00584

416.503 0.00185

427.462 0.00763

431.518 0.00182

529.554 0.0109

409.404 0.00708

441.489 0.00296

417.467 0.000186

441.42 0.00295

473.49 0.224

422.442 0.0029

471.515 0.0000365

475.571 0.000024

407.431 0.00207

388.493 0.00496

384.437 0.00176

445.476 0.00776

473.506 0.000132

477.562 0.000178

453.456 0.000577

368.754 0.406

421.458 0.00878

427.486 0.0464

445.476 0.0072

423.43 0.000489

427.486 0.00191

449.552 0.00324

445.496 0.0025

445.476 0.0497

455.516 0.000174

417.535 0.00592

513.551 0.000119

475.571 0.0000455

457.488 0.0000615

445.476 0.00268

461.544 0.000206

433.441 0.0631

443.505 0.019

473.506 0.000005

473.506 0.000137

477.562 0.000031

477.562 0.000156

425.446 0.0149

485.541 0.000521

519.598 0.07

463.535 0.00112

412.447 0.00133

416.503 0.00121

418.426 0.000593

432.453 0.00465

423.43 0.000533

499.525 0.0000175

446.533 0.00059

444.507 0.000105

469.474 0.00583

484.557 0.00143

488.613 0.000705

466.499 0.000025

432.477 0.0221

399.452 0.0077

434.493 0.0079

416.503 0.00112

Example 2 Apomorphine Induced Deficits in Prepulse Inhibition of theStartle Response in Rats, an In Vivo Test for Antipsychotic Activity

The thought disorders that are characteristic of schizophrenia mayresult from an inability to filter, or gate, sensorimotor information.The ability to gate sensorimotor information can be tested in manyanimals as well as in humans. A test that is commonly used is thereversal of apomorphine-induced deficits in the prepulse inhibition ofthe startle response. The startle response is a reflex to a suddenintense stimulus such as a burst of noise. In this example, rats areexposed to a sudden burst of noise, at a level of 120 db for 40 msec,e.g., the reflex activity of the rats is measured. The reflex of therats to the burst of noise may be attenuated by preceding the startlestimulus with a stimulus of lower intensity, at 3 db to 12 db abovebackground (65 db), which attenuates the startle reflex by 20% to 80%.

The prepulse inhibition of the startle reflex, described above, may beattenuated by drugs that affect receptor signaling pathways in the CNS.One commonly used drug is the dopamine receptor agonist apomorphine.Administration of apomorphine reduces the inhibition of the startlereflex produced by the prepulse. Antipsychotic drugs such as haloperidolprevents apomorphine from reducing the prepulse inhibition of thestartle reflex. This assay can be used to test the antipsychoticefficacy of PDE10 inhibitors, as they reduce the apomorphine-induceddeficit in the prepulse inhibition of startle.

Example 3 Conditioned Avoidance Responding (Car) in Rats, an In VivoTest for Antipsychotic Activity

Conditioned avoidance responding (CAR) occurs, for instance, when ananimal learns that a tone and light predict the onset of a mild footshock. The subject learns that when the tone and light are on, it mustleave the chamber and enter a safe area. All known antipsychotic drugsreduce this avoidance response at doses which do not cause sedation.Examining the ability of test compounds to suppress the conditionedavoidance has been widely used for close to fifty years to screen fordrugs with useful antipsychotic properties.

In this example, an animal is placed in a two-chambered shuttle box andpresented with a neutral conditioned stimulus (CS) consisting of a lightand tone, followed by an aversive unconditioned stimulus (US) consistingof a mild foot shock through a floor grid in the shuttle box chamber.The animal is free to escape the US by running from one chamber to theother, where the grid is not electrified. After several presentations ofthe CS-US pair, the animal typically learns to leave the chamber duringthe presentation of the CS and avoid the US altogether. Animals treatedwith clinically-relevant doses of antipsychotic drugs have a suppressionof their rate of avoidances in the presence of the CS even though theirescape response to the shock itself is unaffected.

Specifically, conditioned avoidance training is conducted using ashuttle box (Med Associates, St. Albans, Vt.). The shuttle box isdivided into 2 equal compartments that each contain a light source, aspeaker that emits an 85 dB tone when activated and an electrified gridthat can deliver a scrambled foot shock. Sessions consist of 20 trialsper day (intertrial interval of 25-40 sec) during which a 10 secillumination and a concurrent 10 sec tone signals the subsequentdelivery of a 0.5 mA shock applied for a maximum of 10 sec. Activeavoidance, defined as the crossing into the opposite compartment duringthe 10 sec conditioning stimuli (light and tone) prevents the deliveryof the shock. Crossing over to the other compartment after the deliveryof the shock terminates shock delivery and is recorded as an escaperesponse. If an animal does not leave the conditioning chamber duringthe delivery of the shock it is recorded as an escape failure. Trainingis continued daily until the avoidance of 16 or more shocks out of 20trials (80% avoidance) on 2 consecutive days is achieved. After thiscriterion is reached the rats are given one day of pharmacologicaltesting. On test day, rats are randomly assigned to experimental groups,weighed and injected intraperitoneally (i.p.) (1 cc tuberculin syringe,26⅜ gauge needle) or per os (p.o.) (18 gauge feeding needle) with eithercontrol or compound solutions. Compounds are injected at 1.0 ml/kg fori.p. and 10 mL/kg for p.o. administration. Compounds can be administeredeither acutely or chronically. For testing, each rat is placed in theshuttle box, and given 20 trials with the same parameters as describedabove for training trials. The number of avoidances, escapes, and escapefailures are recorded.

Example 4 PCP-Induced Hyperactivity (PCP-LMA)

Equipment Used: 4×8 home cage photobeam activity system (PAS) frame fromSan Diego Instruments. Open PAS program and prepare an experimentalsession using the following variables:

Multiphase experiment300 sec/interval (5 min)12 intervals (1 h)Individual on screen switches.Start recording after first beam break.End session after end of interval.

Cage Preparation:

Techniplast™ rat cage with filter top, but no wire lid. Place ˜400 mLbedding and one food pellet in cage and place 250 mL techniplast waterbottle in holder on filter top. Place the prepped cage in the PAS frame.Make sure bedding or pellet doesn't block the photobeams.

Animal Preparation:

Mark rats and record their weights. Bring rats to testing room.

Phase I: Habituation

Start the experiment session. Place the rat in the enclosure. Thecomputer should start recording when it detects the rat breaking thebeam. The computer will record for 1 h. During the habituation phase,prepare risperidone (positive control): Measure out risperidone,calculate final volume at 1 mg/mL concentration and add 1% glacialacetic acid of the final volume to dissolve risperidone. Whenrisperidone is dissolved, add saline to final volume to make aconcentration of 1 mg/mL. Fill syringes (3 mL syringes with 23 g½ needleor oral gavage needle) with Amgen compound solution (5 mL/kg) orrisperidone (1 mL syringe with 23 g½ needle) control (1 mL/kg) s.c.

Phase II: Compound Pre-Treatment

Make sure Phase I has ended. Remove rat from enclosure, start the nextphase using on-screen individual switch, administer compound p.o or i.p.and control s.c. and place rat back in the enclosure. The computershould start recording when it detects the rat breaking the beam. Thecomputer will record for 1 h.

During phase II, prepare pcp: Dissolve pcp in saline to a concentrationof 5 mg/mL.

Fill syringes (1 mL syringes with 26 g3/8 needle) with pcp solution (1mL/kg).

Phase III: Pcp Administration.

Make sure phase II is ended. Remove rat from enclosure, start the nextphase using on-screen individual switch, administer pcp s.c. and placerat back in the enclosure. The computer will record for 1 h.

Clean-Up:

End-session to terminate experiment and so that computer will compiledata. Export raw data to excel file for data analysis. Euthanize ratsand take necessary tissue/sample for PK.

Data Generation:

Export raw data to excel file for data analysis. Total time of movementis recorded as the number of photobeam breaks by the computer. Totaltime of movement (seconds) is combined into 5 minute bins and averagedfor each treatment group for an N of 7-10 animals. Data are analyzed forstatistical significance using a two-way ANOVA followed by aBonferroni's post-hoc test for multiple comparisons.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

The compounds of the present invention may be administered orally,parentally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles, for the treatment of PDE10-relateddiseases, such as acute, inflammatory and neuropathic pain, dental pain,general headache, migraine, cluster headache, mixed-vascular andnon-vascular syndromes, tension headache, general inflammation,arthritis, rheumatic diseases, osteoarthritis, inflammatory boweldisorders, inflammatory eye disorders, inflammatory or unstable bladderdisorders, psoriasis, skin complaints with inflammatory components,chronic inflammatory conditions, inflammatory pain and associatedhyperalgesia and allodynia, neuropathic pain and associated hyperalgesiaand allodynia, diabetic neuropathy pain, causalgia, sympatheticallymaintained pain, deafferentation syndromes, asthma, epithelial tissuedamage or dysfunction, herpes simplex, disturbances of visceral motilityat respiratory, genitourinary, gastrointestinal or vascular regions,wounds, burns, allergic skin reactions, pruritus, vitiligo, generalgastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders. The term parenteral as used herein includes, subcutaneous,intravenous, intramuscular, intrasternal, infusion techniques orintraperitoneally.

Treatment of diseases and disorders herein is intended to also includethe prophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) believed to be in need of preventative treatment, such as, forexample, pain, inflammation and the like.

The dosage regimen for treating PDE10-receptor-mediated diseases,cancer, and/or hyperglycemia with the compounds of this invention and/orcompositions of this invention is based on a variety of factors,including the type of disease, the age, weight, sex, medical conditionof the patient, the severity of the condition, the route ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. Dosage levels of the order from about 0.01 mg to 30 mg perkilogram of body weight per day, preferably from about 0.1 mg to 10mg/kg, more preferably from about 0.25 mg to 1 mg/kg are useful for allmethods of use disclosed herein.

The pharmaceutically active compounds of this invention can be processedin accordance with conventional methods of pharmacy to produce medicinalagents for administration to patients, including humans and othermammals.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 2000mg, preferably from about 1 to 500 mg, more preferably from about 5 to150 mg. A suitable daily dose for a human or other mammal may varywidely depending on the condition of the patient and other factors, but,once again, can be determined using routine methods.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, preferably from about 0.1 to about 10 mg/kg,and more preferably from about 0.25 mg to 1 mg/kg.

Injectable preparations, such as sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known areusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of active ingredient of a compound of theinvention is 0.1 mg to 150 mg administered one to four, preferably oneor two times daily. For topical administration, the active ingredientmay comprise from 0.001% to 10% w/w, e.g., from 1% to 2% by weight ofthe formulation, although it may comprise as much as 10% w/w, butpreferably not more than 5% w/w, and more preferably from 0.1% to 1% ofthe formulation.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, acacia, gelatin, sodium alginate,polyvinyl-pyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, tragacanth gum, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form(including granules, powders or suppositories) or in a liquid form(e.g., solutions, suspensions, or emulsions). The pharmaceuticalcompositions may be subjected to conventional pharmaceutical operationssuch as sterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting, sweetening,flavoring, and perfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or non-racemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, e.g., by formationof diastereoisomeric salts, by treatment with an optically active acidor base. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using active starting materials.These isomers may be in the form of a free acid, a free base, an esteror a salt.

Likewise, the compounds of this invention may exist as isomers, that iscompounds of the same molecular formula but in which the atoms, relativeto one another, are arranged differently. In particular, the alkylenesubstituents of the compounds of this invention, are normally andpreferably arranged and inserted into the molecules as indicated in thedefinitions for each of these groups, being read from left to right.However, in certain cases, one skilled in the art will appreciate thatit is possible to prepare compounds of this invention in which thesesubstituents are reversed in orientation relative to the other atoms inthe molecule. That is, the substituent to be inserted may be the same asthat noted above except that it is inserted into the molecule in thereverse orientation. One skilled in the art will appreciate that theseisomeric forms of the compounds of this invention are to be construed asencompassed within the scope of the present invention.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. The salts include, but are notlimited to, the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methansulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 2-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate, andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulfuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Also encompassed in the scope of the present invention arepharmaceutically acceptable esters of a carboxylic acid or hydroxylcontaining group, including a metabolically labile ester or a prodrugform of a compound of this invention. A metabolically labile ester isone which may produce, for example, an increase in blood levels andprolong the efficacy of the corresponding non-esterified form of thecompound. A prodrug form is one which is not in an active form of themolecule as administered but which becomes therapeutically active aftersome in vivo activity or biotransformation, such as metabolism, forexample, enzymatic or hydrolytic cleavage. For a general discussion ofprodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examplesof a masked carboxylate anion include a variety of esters, such as alkyl(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),aralkyl (for example, benzyl, p-methoxybenzyl), andalkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have beenmasked as arylcarbonyloxymethyl substituted derivatives which arecleaved by esterases in vivo releasing the free drug and formaldehyde(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidicNH group, such as imidazole, imide, indole and the like, have beenmasked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs,Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use. Esters of acompound of this invention, may include, for example, the methyl, ethyl,propyl, and butyl esters, as well as other suitable esters formedbetween an acidic moiety and a hydroxyl containing moiety. Metabolicallylabile esters, may include, for example, methoxymethyl, ethoxymethyl,iso-propoxymethyl, α-methoxyethyl, groups such asα-((C₁-C₄)alkyloxy)ethyl, for example, methoxyethyl, ethoxyethyl,propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethylgroups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C₁-C₃alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl,isopropylthiomethyl, etc.; acyloxymethyl groups, for example,pivaloyloxymethyl, α-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; orα-acyloxy-α-substituted methyl groups, for example α-acetoxyethyl.

Further, the compounds of the invention may exist as crystalline solidswhich can be crystallized from common solvents such as ethanol,N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms ofthe compounds of the invention may exist as polymorphs, solvates and/orhydrates of the parent compounds or their pharmaceutically acceptablesalts. All of such forms likewise are to be construed as falling withinthe scope of the invention.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are given at the same time or differenttimes, or the therapeutic agents can be given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A method of treating conditions that may be treated with PDE10inhibitors comprising the step of administering to a subject atherapeutically effective amount of a compound of formula I:

or any pharmaceutically-acceptable salt thereof, wherein: Each of X¹,X², X³, X⁴, and X⁵ is independently N or C; wherein no more than two ofX¹, X², X³ and X⁴ are N; Each of X⁶, X⁷, X⁹, and X¹⁰ is independently Nor C; each of X⁸ and X¹¹ is C; wherein no more than three of X⁶, X⁷, X⁹,and X¹⁰ are N; Y is NH, NR⁵, CH(OH), C(═O), —CR^(a)R^(b), or CF₂; oralternatively Y and R³ form a 5- to 6-membered ring fused to the ringcontaining both said Y and R³; Z is NH, NR⁶, S, SO, SO₂, O, or C;wherein Z is only C when X⁵ is N; m is 0, 1, 2, 3 or 4; n is 0, 1 or 2;p is 0, 1 or 2; R¹ is selected from the group consisting of (a) H, F,Cl, Br, I, C₁₋₈alk, C₁₋₄haloalk, —OR^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —C(═O)NR^(a)R^(a), —C(═O)R^(d), —C(═O)—O—R^(a),—OR^(c), —NR^(a)R^(c), —N(R^(c))C(═O)R^(b), —N(R^(a))C(═O)R^(c),—C(═O)NR^(a)R^(b), or —C(═O)NR^(a)R^(c); (b) a saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedmonocyclic ring or a saturated, partially-saturated or unsaturated 8-,9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said ringcontains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms selected from Oand S, and wherein each said ring is substituted by 0, 1, 2 or 3 groupsselected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk,CN, —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —NR^(a)R^(c),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆ alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁷, R⁸ and oxo; (c) group-L-R⁷, wherein L is CH₂, NH, N(C₁₋₄alk), —C(═O)NR^(a)R^(a)(C₁₋₄alk), O,S, S═O, or S(═O)₂; or (d) C₁₋₆alk substituted by 0, 1, 2 or 3 groupsselected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk,CN, —C(═O)R^(b), —C(═O)OR^(b), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a), R⁸ and oxo;R² is, independently in each instance, F, Cl, Br, CN, OH, OC₁₋₄alk,C₁₋₄alk or C₁₋₄haloalk; R³ is, independently in each instance, F, Cl,Br, CN, OH, OC₁₋₄alk, C₁₋₄alk, C₁₋₄haloalk, or —NR^(a)C₁₋₄alk; R⁴ isindependently in each instance, F, Cl, CH₃, CN, CF₃, CHF₂, CH₂F, OR^(a),or NR^(a)R^(a); R⁵ is C₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), or R^(c); R⁶ isC₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), or R^(c); R⁷ is a saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing0, 1, 2 or 3 N atoms and 0 or 1 atoms selected from O and S, which issubstituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁸ and oxo; R⁸ is aC₁₋₆alk substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo; R^(a) isindependently, at each instance, H or R^(b); R^(b) is independently, ateach instance, phenyl, benzyl, or C₁₋₆alk, wherein said phenyl, benzyl,and C₁₋₆alk are being substituted by 0, 1, 2 or 3 substituents selectedfrom halo, C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk,—OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk; R^(c) is a C₀₋₄alk-linkedsaturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or7-membered monocyclic; or 8-, 9-, 10-, 11-, or 12-membered bicyclic ringcontaining 0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S,wherein said C₀₋₄alk and said ring moiety may be substituted by 0, 1, 2or 3 groups selected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, R⁷, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo; and R^(d) is anitrogen-linked saturated, partially-saturated, or unsaturated 5-, 6- or7-membered ring heterocycle containing the linking nitrogen and 0, 1 or2 additional nitrogen atoms and containing 0 or 1 sulfur or oxygen atom,the heterocycle being substituted by 0, 1, 2 or 3 substituents selectedfrom oxo, halo, C₁₋₄alk, C₁₋₃haloalk, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, and—N(C₁₋₄alk)C₁₋₄alk.
 2. The method of claim 1 wherein said condition isselected from the group consisting of psychoses, Parkinson's disease,dementias, obsessive compulsive disorder, tardive dyskinesia, choreas,depression, mood disorders, impulsivity, drug addiction, attentiondeficit/hyperactivity disorder (ADHD), depression with parkinsonianstates, personality changes with caudate or putamen disease, dementiaand mania with caudate and pallidal diseases, and compulsions withpallidal disease.
 3. The method of claim 1 wherein said condition isselected from the group consisting of obesity, schizophrenia,Huntington's disease, bipolar disorder, and obsessive-compulsivedisorder.
 4. A method of treating conditions that may be treated withPDE10 inhibitors comprising the step of administering to a subject atherapeutically effective amount of a compound of formula II:

or any pharmaceutically-acceptable salt thereof, wherein: Z is NH, NR⁶,S or O; m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; p is 0, 1 or 2; y is 0, 1,2, 3 or 4; X¹ is N or C; X⁵ is N or C; Ring A is acarbon-linked-saturated, carbon-linked-partially-saturated, orcarbon-linked-unsaturated 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing0 or 1 S or O atom; or a nitrogen-linked-saturated,nitrogen-linked-partially-saturated, or nitrogen-linked-unsaturated 4-,5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring heterocycle containingthe linking nitrogen and 0, 1 or 2 additional N atoms and containing 0or 1 S or O atom; R² is, independently in each instance, F, Cl, Br, CN,OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk; R³ is, independently in eachinstance, F, Cl, Br, CN, OH, OC₁₋₄alk, C₁₋₄alk, C₁₋₄haloalk, or—NR^(a)C₁₋₄alk; R⁴ is independently in each instance, F, Cl, CH₃, CN,CF₃, CHF₂, CH₂F, OR^(a), or NR^(a)R^(a); R⁵ is C₁₋₈alk, C₁₋₄haloalk,—C(═O)R^(b), or R^(c); R⁶ is C₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), orR^(c); R⁷ is a saturated, partially-saturated or unsaturated 3-, 4-, 5-,6-, or 7-membered monocyclic or 8-, 9-, 10-, 11-, or 12-memberedbicyclic ring containing 0, 1, 2, 3, or 4 N atoms and 0 or 1 atomsselected from O and S, which is substituted by 0, 1, 2 or 3 groupsselected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk,CN, —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁸ and oxo; R⁸ is aC₁₋₆alk substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo; R⁹ isindependently selected from the group consisting of H, F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—NR^(a)R^(c), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a), —NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a),—C₁₋₆ alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁷, R⁸ and oxo; R^(a) isindependently, at each instance, H or R^(b); R^(b) is independently, ateach instance, phenyl, benzyl or C₁₋₆alk, the phenyl, benzyl and C₁₋₆alkbeing substituted by 0, 1, 2 or 3 substituents selected from halo,C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk,or —N(C₁₋₄alk)C₁₋₄alk; and R^(c) is a C₀₋₄alk-linked saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which issubstituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, R⁷, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo.
 5. The method ofclaim 4 wherein said condition is selected from the group consisting ofpsychoses, Parkinson's disease, dementias, obsessive compulsivedisorder, tardive dyskinesia, choreas, depression, mood disorders,impulsivity, drug addiction, attention deficit/hyperactivity disorder(ADHD), depression with parkinsonian states, personality changes withcaudate or putamen disease, dementia and mania with caudate and pallidaldiseases, and compulsions with pallidal disease.
 6. The method of claim4 wherein said condition is selected from the group consisting ofobesity, schizophrenia, Huntington's disease, bipolar disorder, andobsessive-compulsive disorder.
 7. A method of treating conditions thatmay be treated with PDE10 inhibitors comprising the step ofadministering to a subject a therapeutically effective amount of acompound of formula III:

or any pharmaceutically-acceptable salt thereof, wherein: Z is NH, NR⁶,S or O; m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; p is 0, 1 or 2; y is 0, 1,2, 3 or 4; X¹ is N or C; X⁵ is N or C; Ring A is acarbon-linked-saturated, carbon-linked-partially-saturated, orcarbon-linked-unsaturated 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing0 or 1 S or O atom; or a nitrogen-linked-saturated,nitrogen-linked-partially-saturated, or nitrogen-linked-unsaturated 4-,5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring heterocycle containingthe linking nitrogen and 0, 1 or 2 additional N atoms and containing 0or 1 S or O atom; R² is, independently in each instance, F, Cl, Br, CN,OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk; R³ is, independently in eachinstance, F, Cl, Br, CN, OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk; R⁴ isindependently in each instance, F, Cl, CH₃, CN, CF₃, CHF₂, CH₂F, OR^(a),or NR^(a)R^(a); R⁵ is C₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), or R^(c); R⁶ isC₁₋₈alk, C₁₋₄haloalk, —C(═O)R^(b), or R^(c); R⁷ is a saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing0, 1, 2, 3, or 4 N atoms and 0 or 1 atoms selected from O and S, whichis substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁸ and oxo; R⁸ is aC₁₋₆alk substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆ alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo; R⁹ isindependently selected from the group consisting of H, F, Cl, Br,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—NR^(a)R^(c), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—N(R^(a))C(═O)NR^(a)R^(a), —N(R^(a))C(═NR^(a))NR^(a)R^(a),—N(R^(a))S(═O)₂R^(b), —N(R^(a))S(═O)₂NR^(a)R^(a),—NR^(a)C₂₋₆alkNR^(a)R^(a), —NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a),—C₁₋₆ alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), R⁷, R⁸ and oxo; R^(a) isindependently, at each instance, H or R^(b); R^(b) is independently, ateach instance, phenyl, benzyl or C₁₋₆alk, the phenyl, benzyl and C₁₋₆alkbeing substituted by 0, 1, 2 or 3 substituents selected from halo,C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk,or —N(C₁₋₄alk)C₁₋₄alk; and R^(c) is a C₀₋₄alk-linked saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or 8-, 9-, 10-, 11-, or 12-membered bicyclic ring containing0, 1, 2 or 3 N atoms and 0 or 1 atom selected from O and S, which issubstituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, R⁷, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo.
 8. The method ofclaim 7 wherein said condition is selected from the group consisting ofpsychoses, Parkinson's disease, dementias, obsessive compulsivedisorder, tardive dyskinesia, choreas, depression, mood disorders,impulsivity, drug addiction, attention deficit/hyperactivity disorder(ADHD), depression with parkinsonian states, personality changes withcaudate or putamen disease, dementia and mania with caudate and pallidaldiseases, and compulsions with pallidal disease.
 9. The method of claim7 wherein said condition is selected from the group consisting ofobesity, schizophrenia, Huntington's disease, bipolar disorder, andobsessive-compulsive disorder.
 10. The method as in any one of claims 1,4, and 7, in which said compound of formula I, II, or III, is selectedfrom the group consisting of:(1H-Benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone;(S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone;[4-(3-Chloro-pyrazin-2-yloxy)-phenyl]-(6-fluoro-1H-benzoimidazol-2-yl)-methanone;(1-Methyl-1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)-methanone;(1-Isopropyl-1H-benzo[d]imidazol-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)-methanone;4-(3-(4-((1H-benzo[d]imidazol-2-yl)difluoromethyl)phenoxy)pyrazin-2-yl)morpholine(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-hydroxypiperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxypiperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-methoxypiperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(R)-(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2,6-dimethylmorpholino)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-methylpiperazin-1-yl)pyrazin-2-yloxy)phenyl)methanone;1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperazin-1-yl)ethanone;1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-4-carbonitrile;(1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-ylamino)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-3-ylamino)pyrazin-2-yloxy)phenyl)methanone;(4-(3-(1,4-oxazepan-4-yl)pyrazin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(methoxymethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-4-one;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(2-hydroxyethyl)piperazin-1-yl)pyrazin-2-yloxy)phenyl)methanone;ethyl2-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperazin-1-yl)acetate;(1H-benzo[d]imidazol-2-yl)(4-(3-(6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-methoxypiperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;8-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-2-methyl-2,8-diazaspiro[4.5]decan-1-one;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-morpholinopiperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxypyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methylpiperazin-2-one;(S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-(hydroxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(3-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)pyrazin-2-yloxy)phenyl)methanone;(R)-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-(hydroxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(2-hydroxyethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-3-carbonitrile;(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;ethyl1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-4-carboxylate;methyl1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carboxylate;ethyl1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-3-carboxylate;(1H-benzo[d]imidazol-2-yl)(4-(3-(3-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxypyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(1-hydroxyethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-4-carboxylicacid;(1H-benzo[d]imidazol-2-yl)(4-(3-(3-(2-hydroxyethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(hydroxymethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(3-(2-hydroxypropan-2-yl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-6-methylpiperazin-2-one;(1H-imidazo[4,5-b]pyridin-2-yl)(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone;(4-(3-chloropyrazin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone;(4-(3-chloropyrazin-2-yloxy)phenyl)(7-fluoro-1H-benzo[d]imidazol-2-yl)methanone;(4-(3-chloropyrazin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxyazetidin-1-yl)pyrazin-2-yloxy)phenyl)methanone;(S)-N-(4-(3-(2-(Methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(Tetrahydro-2H-pyran-3-ylamino)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;(S)-2-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-2-yl)propan-2-ol;1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-4-methylpiperidin-4-ol;Benzo[d]thiazol-2-yl(4-(3-morpholinopyrazin-2-yloxy)phenyl)methanone;N-(4-(3-Chloropyrazin-2-yloxy)phenyl)-6-fluorobenzo[d]thiazol-2-amine;N-(4-(3-morpholinopyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine;5-fluoro-N-(4-(3-morpholinopyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine;N-(4-(3-morpholinopyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;2-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)propan-2-ol;1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-ol;N-(4-(3-(pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-3-ol;1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-4-carbonitrile;1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperazin-1-yl)ethanone;N-(4-(3-(4-methylpiperazin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;2-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)-1,1,1-trifluoropropan-2-ol;N-(4-(3-(2,6-dimethylmorpholino)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-((3-(1,1-dioxido-4-thiomorpholinyl)-2-pyrazinyl)oxy)phenyl)-1,3-benzothiazol-2-amine;(S)-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-2-yl)methanol;N-(4-(3-(azetidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)azetidine-3-carboxylicacid;2-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperazin-1-yl)ethanol;N-(4-(3-(6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-4-carboxamide;N-(4-(3-(2-methyl-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;methyl1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)azetidine-3-carboxylate;1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;(R)-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-3-yl)methanol;2-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)ethanol;N-(4-(3-(4-(methoxymethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(3-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)methanol;4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperazin-2-one;4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-1-isopropylpiperazin-2-one;N-(4-(3-(4-methoxypiperidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)azetidine-3-carbonitrile;4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-6-methylpiperazin-2-one;1-(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-4-yl)ethanol;methyl1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidine-3-carboxylate;(1-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-2-yl)methanol;N-(4-(3-(3-(methoxymethyl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-chloropyrazin-2-yloxy)phenyl)-7-fluorobenzo[d]thiazol-2-amine;N-(4-(3-chloropyrazin-2-yloxy)phenyl)-6-fluorobenzo[d]thiazol-2-amine;N-(4-(3-chloropyrazin-2-yloxy)phenyl)-5-fluorobenzo[d]thiazol-2-amine;N-(4-(3-chloropyrazin-2-yloxy)-2-fluorophenyl)benzo[d]thiazol-2-amine;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(trifluoromethyl)pyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(4-methoxybenzyloxy)pyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyridin-2(1H)-one;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-methylpyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone;4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)benzonitrile;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-methylpyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(2-methylpyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2,6-dimethoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(3-methoxypyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxyphenyl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxyquinolin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(5-fluoro-2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(5-fluoro-1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(5-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxypyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(6-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone;3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)benzonitrile;methyl4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)benzoate;4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)benzoicacid;(1H-benzo[d]imidazol-2-yl)(4-(3-(3-methoxyphenyl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(quinolin-4-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(quinolin-5-yl)pyrazin-2-yloxy)phenyl)methanone;(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)(1H-imidazo[4,5-b]pyridin-2-yl)methanone;2-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-4,4-dimethylcyclohex-2-enone;1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone;(1-(2-fluoroethyl)-1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanone;N-(4-(3-(2-methylpyridin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enone;3-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)cyclohex-2-enol;N-(4-(3-(6-morpholinopyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(4-morpholinophenyl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(6-methylpyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;5-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)picolinonitrileN-(4-(3-(pyrimidin-5-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(2-methoxypyrimidin-5-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(6-chloropyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;(5-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyridin-2-yl)methanol;N-(4-(3-(quinolin-5-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(pyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(3-methoxypyridin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(3-methoxyphenyl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;7-fluoro-N-(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(2-methoxypyridin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;6-fluoro-N-(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;5-fluoro-N-(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(5-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(2-fluoro-4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(2-fluoro-4-(3-(2-fluoropyridin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;tert-butyl4-(3-(4-(benzo[d]thiazol-2-ylamino)-3-fluorophenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate;(1H-benzo[d]imidazol-2-yl)(4-(3-methoxypyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-isopropoxypyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-isobutoxypyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(cyclopropylmethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2,2,2-trifluoroethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxyethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-2-ylmethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-phenoxypyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-3-yloxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(but-2-ynyloxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(4-methylthiazol-5-yl)ethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-((tetrahydrofuran-3-yl)methoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-morpholinoethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(pyrrolidin-1-yl)ethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(dimethylamino)ethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(1-methylpyrrolidin-2-yl)ethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-4-ylmethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-(pyridin-2-yl)ethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(3-(pyridin-3-yl)propoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(pyridin-3-ylmethoxy)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-propoxypyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-imidazo[4,5-b]pyridin-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;(6-fluoro-1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;(1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;(6-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;(5-fluoro-1-methyl-1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;1H-benzimidazol-2-yl(4-((3-(tetrahydro-2H-pyran-3-yl)-2-pyrazinyl)oxy)-phenyl)methanone;1H-Benzimidazol-2-yl(4-(3-(4-methoxy-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)phenyl)methanone;1H-benzimidazol-2-yl(4-((3-(cis-4-hydroxycyclohexyl)-2-pyrazinyl)oxy)phenyl)methanone;and1H-benzimidazol-2-yl(4-((3-(trans-4-hydroxycyclohexyl)-2-pyrazinyl)oxy)phenyl)methanone;cis-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;trans-(1H-benzo[d]imidazol-2-yl)(4-(3-(3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;cis-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;trans-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;N-(4-(3-(Tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanone;4-(2-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cyclohexanone;(1H-Benzo[d]imidazol-2-yl)(4-(3-((1s,4s)-4-hydroxy-4-methylcyclohexyl)pyridin-2-yloxy)phenyl)methanone;(1H-Benzo[d]imidazol-2-yl)(4-(3-((1r,4r)-4-hydroxy-4-methylcyclohexyl)pyridin-2-yloxy)phenyl)methanone;(1H-Benzo[d]imidazol-2-yl)(4-(3-(oxepan-4-yl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(4,4-difluorocyclohex-1-enyl)pyrazin-2-yloxy)phenyl)methanone;4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)tetrahydro-2H-pyran-4-carbonitrile;N-methyl-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)tetrahydro-2H-pyran-4-ol;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-fluorotetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;N-(4-(3-(4-fluorotetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;1-tert-butyl 4-methyl4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1,4-dicarboxylate;tert-butyl4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-4-(hydroxymethyl)piperidine-1-carboxylate;N-(4-(3-(Tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine;N-(4-(3-(Tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;7-Methoxy-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine;3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)cyclohexanone;4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)tetrahydro-2H-pyran-4-carbonitrile;methyl4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)tetrahydro-2H-pyran-4-carboxylate;(1H-benzo[d]imidazol-2-yl)(4-(3-(4-hydroxytetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;6-fluoro-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(2-fluoro-4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(2-fluoro-4-(pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;7-fluoro-N-(4-(pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;5-fluoro-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;5-fluoro-N-(4-(pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;(1H-benzo[d]imidazol-2-yl)(4-(3-cyclopentylpyrazin-2-yloxy)phenyl)methanone;N-(4-(3-(tetrahydrofuran-3-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;1H-benzo[d]imidazole-2-yl(4-(3-(tetrahydro-2H-thiopyran-4-yl)pyrazin-2-yloxy)phenyl)methanone;N-(4-(3-cyclopentylpyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(1-(2-fluoroethyl)piperidin-4-yl)pyrazin-2-yloxy)phenyl)methanone;methyl4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate;1-(4-(3-(4-((1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;(1H-benzo[d]imidazol-2-yl)(4-(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)phenyl)methanol;(1H-benzo[d]imidazol-2-yl)(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)methanone;1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)perdeuteroethanone;1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-methoxyethanone;1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-methoxyethanone;1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;N-(4-(3-(1-(2-fluoroethyl)piperidin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;N-(4-(3-(1-methylpiperidin-4-yl)pyrazin-2-yloxy)phenyl)benzo[d]thiazol-2-amine;1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-1-oxopropan-2-ylacetate;1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-hydroxypropan-1-one;1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidin-1-yl)ethanone;1-(3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)pyrrolidin-1-yl)ethanone;1-(4-(3-(4-(1-methyl-1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;2-methoxy-1-(4-(3-(4-(1-methyl-1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;2-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-oxoethyl acetate;1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-(dimethylamino)ethanone;1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-(dimethylamino)ethanone;3-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-3-oxopropanenitrile;1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)-2-fluorophenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;1-(4-(3-(6-(benzo[d]thiazol-2-ylamino)pyridin-3-yloxy)pyrazin-2-yl)piperidin-1-yl)ethanone;1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidin-1-yl)ethanone;1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone;4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methyl-5,6-dihydropyridin-2(1H)-one;4-(3-(4-(1H-Benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methylpiperidin-2-one;3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-phenethylpyrazine-2-carboxamide;3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(4-(trifluoromethyl)phenethyl)pyrazine-2-carboxamide;(S)-3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(1-methoxypropan-2-yl)pyrazine-2-carboxamide;3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(2-(pyridin-2-yl)ethyl)pyrazine-2-carboxamide;3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(2-hydroxyethyl)pyrazine-2-carboxamide;3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(1-(pyridin-2-yl)propan-2-yl)pyrazine-2-carboxamide;3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-(1-benzylcyclopropyl)pyrazine-2-carboxamide;(R)-1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;(S)-1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carbonitrile;(R)-ethyl1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-3-carboxylate;(S)-ethyl1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-3-carboxylate;(S)-methyl1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carboxylate;(R)-methyl1-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)pyrrolidine-3-carboxylate;(R)-4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-6-methylpiperazin-2-one;(S)-4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)-6-methylpiperazin-2-one;(1H-benzo[d]imidazol-2-yl)(4-(3-((1R,3S)-3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-((1S,3R)-3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;(1S,3R)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;(1R,3S)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;(1H-benzo[d]imidazol-2-yl)(4-(3-((1S,3S)-3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;(1H-benzo[d]imidazol-2-yl)(4-(3-((1R,3R)-3-hydroxycyclohexyl)pyrazin-2-yloxy)phenyl)methanone;(1S,3S)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;(1R,3R)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanol;(R)-1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;(S)-1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;(R)-1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;(S)-1-(4-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one;(R)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanone;(S)-3-(3-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyrazin-2-yl)cyclohexanone;or any pharmaceutically-acceptable salt thereof.
 11. The method of claim6, in which said compound of formula II is:

or a pharmaceutically acceptable salt thereof, wherein said condition isschizophrenia or Huntington's disease.
 12. The method of claim 6, inwhich said compound of formula II is:

or a pharmaceutically acceptable salt thereof, and wherein saidcondition is schizophrenia or Huntington's disease.
 13. The method ofclaim 6, in which said compound of formula II is:

or a pharmaceutically acceptable salt thereof, and wherein saidcondition is schizophrenia or Huntington's disease.
 14. The method ofclaim 6, in which said compound of formula II is:

or a pharmaceutically acceptable salt thereof, and wherein saidcondition is schizophrenia or Huntington's disease.
 15. The method ofclaim 6, in which said compound of formula II is:

or a pharmaceutically acceptable salt thereof, and wherein saidcondition is schizophrenia or Huntington's disease.
 16. The method ofclaim 6, in which said compound of formula II is:

or a pharmaceutically acceptable salt thereof, and wherein saidcondition is schizophrenia or Huntington's disease.
 17. The method ofclaim 6, in which said compound of formula II is:

or a pharmaceutically acceptable salt thereof, and wherein saidcondition is schizophrenia or Huntington's disease.
 18. The method ofclaim 6, in which said compound of formula II is:

or a pharmaceutically acceptable salt thereof, and wherein saidcondition is schizophrenia or Huntington's disease.